Novel Membrane Emulsification E-Book

Guanghui Ma

• Herausgeber: Wiley-VCH GmbH
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 574

Veröffentlichungsjahr: 2023

Beschreibung

Novel Membrane Emulsification

Comprehensive resource presenting state-of-the-art of membrane emulsification technology, from principle to practice, with focus on biomedical applications

Novel Membrane Emulsification: Principles, Preparation, Processes, and Bioapplications provides comprehensive coverage of membrane emulsification technology by summarizing the principle, preparation, and bioapplications through utilizing uniform particle size, introducing recent development in preparation and applications in the controlled release and delivery of protein/peptide, anticancer drugs and vaccines, and in the bioseparation media and cell culture carriers, and discussing direct, rapid, and rotary membrane emulsification equipments.

Novel Membrane Emulsification includes information on:

• Preparation of hydrophobic microspheres from O/W emulsion, hydrophilic microspheres from W/O emulsion, and microcapsules/composite microspheres from double emulsions, covering preparation from monomer and preformed polymer systems
• Preparation of small particles by rapid membrane emulsification process
• Applications of uniform particles in sustained release of protein/peptide drugs, covering strategies to improve encapsulation efficiency and maintain bioactivity of drugs
• Applications of uniform particles in anticancer drug and vaccine delivery including personalized therapeutic vaccine
• Applications of uniform particles in protein separation, covering uniform agarose microsphere for protein separation and super-porous microsphere for vaccine separation

Novel Membrane Emulsification is an essential resource for scientists and researchers in multiple fields, particularly chemistry, chemical engineering, and materials science, to advance this technique and produce novel materials with controlled characteristics. The text is also a valuable learning resource for biomedical science and bioengineering researchers and students.

Leseprobe

Table of Contents

Cover

Title Page

Copyright

Preface

1 Membrane Emulsification Process: Principle and Model

1.1 Introduction

1.2 Cross‐Flow Membrane Emulsification

1.3 Premix Membrane Emulsification

1.4 Summary

References

2 Preparation of Hydrophobic Microspheres From O/W Emulsion

2.1 Introduction

2.2 Preparation from Monomer System

2.3 Preparation from Performed Polymer System

2.4 Morphology Control of Microspheres

2.5 Summary

References

3 Preparation of Hydrophilic Polymer Microspheres from W/O Emulsion

3.1 Introduction

3.2 Membrane Modification and Preparation

3.3 Preparation Microparticles from Monomer System

3.4 Preparation Microparticles from Preformed Polymer System

3.5 Other Hydrophilic Microspheres Prepared by Membrane Emulsification

3.6 Summary

References

4 Preparation of Uniform Microcapsules and Microspheres from W/O/W Double Emulsion

4.1 Introduction

4.2 Preparation of Uniform Microcapsules

4.3 Preparation of Composite Microspheres

4.4 Summary

References

5 Rapid Membrane Emulsification Process for Preparation of Small Microspheres

5.1 Introduction

5.2 Preparation of Hydrophobic Microspheres from O/W Emulsion

5.3 Preparation of Hydrophilic Microspheres from W/O Emulsion

5.4 Preparation of Microcapsule from Double Emulsion

5.5 Summary

References

6 Applications of Uniform Particles in Sustained Release of Drugs

6.1 Introduction

6.2 Synthetic Polymer (PLA, PLGA, and PELA)

6.3 Natural Polymer (Polysaccharide) Chitosan

6.4 Summary

References

7 Applications of Uniform Particles for Targeted Delivery of Anticancer Drugs

7.1 Introduction

7.2 Influence of Physical and Chemical Particle Properties on Antitumor Efficacy

7.3 Classical Strategies for Targeting Tumor Tissues

7.4 Novel Biomimetic Delivery Strategies

7.5 Summary

References

8 Applications of Uniform Particles in Vaccine Formulations

8.1 Introduction

8.2 Adjuvant and Delivery System: Assembling the Vaccine Components

8.3 Physicochemical Traits for the Enhanced Vaccination

8.4 Connecting the Dots: Strengthening on the Multi‐Scale Delivery of Vaccines

8.5 Summary

References

9 Applications of Uniform Microspheres and Super‐porous Microspheres in Biochemical Engineering

9.1 Introductions

9.2 Uniform Microspheres for Chromatographic Media

9.3 Super‐Porous Microspheres for Vaccine Separation

9.4 Uniform Microspheres for Cell Culture

9.5 Summary

References

10 Membrane Emulsification Equipment and Industrialization

10.1 Introduction

10.2 Cross‐flow Membrane Emulsification Equipment

10.3 Premix Membrane Emulsification Equipment

10.4 Rotary Membrane Emulsification Equipment

10.5 Industrialization – Case Report

10.6 Summary

References

Index

End User License Agreement

List of Tables

Chapter 2

Table 2.1 Standard recipe for membrane emulsification.

Table 2.2 Standard recipe and results to prepare P(GMA‐EGDMA) microsphere (m...

Table 2.3 Standard recipe for two‐step emulsification and polymerization to ...

Chapter 3

Table 3.1 The effect of the modified layer on the pore size and porosity of ...

Table 3.2 CV values of emulsions prepared by using modified SPG membranes fo...

Table 3.3 The contact angles between water and the surface of the modified S...

Table 3.4 Summaries of hydrophobically modified membranes and hydrophobic me...

Table 3.5 Preparation results of microspheres by the membrane with different...

Table 3.6 Lipase‐loaded amount and specific activity of lipase‐loaded micros...

Chapter 4

Table 4.1 Relationship between percentage weight of inner aqueous phase to o...

Table 4.2 Effect of PVP Amount on the Polymerization Results of Composite Pa...

Chapter 6

Table 6.1 Characterization of OH‐RVC‐MS, COOH‐RVC‐MS, and COOR‐RVC‐MS (resul...

Table 6.2 Characteristics of PLGA microspheres prepared by different dicatio...

Chapter 9

Table 9.1 Theoretical plate number (

N

), tailing factor (

F

(10%)), and resolu...

Table 9.2 Theoretical plate number, tailing factor (10%), and resolution of ...

Table 9.3 Comparison of HB‐VLPs purification on different anion‐exchange med...

Chapter 10

Table 10.1 Critical factors affecting the size uniformity of emulsion.

List of Illustrations

Chapter 1

Figure 1.1 Two basic forms of membrane emulsification. (a) Cross‐flow MET. (...

Figure 1.2 Growth of droplets on surface of SPG membrane.

Figure 1.3 Droplets' spontaneous detaching and adhering behaviors.

Figure 1.4 Droplets distributions at different PVA concentrations.

Figure 1.5 Interfacial tension of oil–water phase at different PVA concentra...

Figure 1.6 Droplets distributions at different SDS concentrations.

Figure 1.7 Droplets distributions at different SDS concentrations.

Figure 1.8 Force analysis of droplets on outlet of membrane pore.

Figure 1.9 Schematic representation of contact line (top view) for a circula...

Figure 1.10 Torques and forces on droplet at membrane outlet. Source: Hao et...

Figure 1.11 Influence of continuous phase flow velocity on droplet size dist...

Figure 1.12 The development of torques on global droplet at different contin...

Figure 1.13 The development of torques on global droplet at different transm...

Figure 1.14 Influence of transmembrane pressure on droplet size distribution...

Figure 1.15 The development of torques on global droplet at different viscos...

Figure 1.16 Droplet size distribution of dispersed phase with different visc...

Figure 1.17 The development of torques on global droplet of paraffin by usin...

Figure 1.18 The droplet size distribution of paraffin by using SDS, Tween 20...

Figure 1.19 The development of torques on global droplet by different disper...

Figure 1.20 The droplet size distribution of different dispersed phase with ...

Figure 1.21 The microdynamic behavior of droplet simulated by CFD. Source: A...

Figure 1.22 Droplet deformation process simulated by CFX: (a) the wall conta...

Figure 1.23 Deformation of droplets on surface of different membrane pores: ...

Figure 1.24 Shape of droplets simulated by Surface Evolver. Source: Rayner e...

Figure 1.25 Movement of droplets simulated by Lattice Boltzmann method. Sour...

Figure 1.26 Schematic representation of the dumbbell‐shaped droplet in a 3D ...

Chapter 2

Figure 2.1 Typical preparation procedure of uniform hydrophobic microspheres...

Figure 2.2 SEM photos of polyDVB microspheres prepared by heptane porogen. S...

Figure 2.3

Optical microscopy

(

OM

) and

scanning electron microscopy

(

SEM

) of...

Figure 2.4 Typical OM and SEM photos of P(GMA‐EGDMA) microsphere. (a) OM ima...

Figure 2.5 Schematic diagram showing the preparation of uniform droplets con...

Figure 2.6 Typical SEM micrographs of microspheres prepared by membrane emul...

Figure 2.7 SEM micrographs of PHEMA microspheres with different microstructu...

Figure 2.8 Schematic illustration of (a) stirred vessel membrane emulsificat...

Figure 2.9

Transmission electron microscopy

(

TEM

) photos of PST/PMMA composi...

Figure 2.10 TEM of different structure with presence of LOH as PMMA/PST rati...

Figure 2.11 Composite microspheres of polyurethane and polystyrene or polyac...

Figure 2.12 The chemical structure of the PIP BANI‐M, and the SEM micrograph...

Figure 2.13 SEM photographs of drug‐loaded microspheres with different size....

Figure 2.14 Fe

3

O

4

polymer particles prepared by different emulsification met...

Figure 2.15 Schematic depiction of the

Shirasu porous glass

(

SPG

) membrane e...

Figure 2.16 Principle of formation of porous polymer particle.

Figure 2.17 Effect of crosslinker amount on phase separation between polymer...

Figure 2.18 SEM showing effect of crosslinker amount on pore size and specif...

Figure 2.19 OM and SEM micrographs of polydivinylbenzene microspheres. Sourc...

Figure 2.20 Turbidity development with polymerization time (a) and schematic...

Figure 2.21 SEM (up) of polydivinylbenzene microspheres, and the development...

Figure 2.22 SEM micrographs of polydivinylbenzene microspheres (up), and the...

Figure 2.23 Schematic representation of formation of heterogeneous structure...

Figure 2.24 PGMA polar microspheres using different stabilizers. (a) gelatin...

Figure 2.25 SEM micrographs of particles as functions of LOH amount and poly...

Figure 2.26 TEM micrographs of particles as functions of LOH amount and poly...

Figure 2.27 Initial and final states for morphology development of a three‐c...

Chapter 3

Figure 3.1 Schematic illustration of the principle of hydrophobic modificati...

Figure 3.2 The effect of KP‐18C concentration on hydrophobicity of SPG membr...

Figure 3.3

Scanning electron microscopy

(

SEM

) photographs of chitosan micros...

Figure 3.4 Contact angles of water on the membrane surfaces: (a) unmodified ...

Figure 3.5 Effect of the types and concentrations of the hydrophobic modific...

Figure 3.6 The effect type of modifiers on hydrophobicity of SPG membrane af...

Figure 3.7 Morphologies of PTFE membrane prepared by sintering electrospun (...

Figure 3.8 Schematic diagram of PTFE nanofiber membrane preparation process....

Figure 3.9 The optical microscope pictures and droplet size distributions of...

Figure 3.10 SEM micrographs of the cross‐section of PVDF membranes (concentr...

Figure 3.11 SEM micrographs of the outer surface of PVDF membranes (concentr...

Figure 3.12 SEM images of (a) surface structure and (b) inner structure of P...

Figure 3.13 Optical micrographs of W/O emulsion prepared by direct membrane ...

Figure 3.14 SEM photographs of membranes: (a) 1.22 μm EP membrane, (b) 2.77 ...

Figure 3.15 Photographs of contact angles of the water droplets on the surfa...

Figure 3.16 Optical micrographs of agarose microspheres prepared by (a) unmo...

Figure 3.17 Schematic illustration of PNIPAM temperature‐sensitive mechanism...

Figure 3.18 Schematic illustration of preparation of monodisperse PNIPAM mic...

Figure 3.19 SEM image of air‐dried PNIPAM microspheres (a) and microcapsules...

Figure 3.20 Dependence of porous structure of P(NIPAM‐

co

‐AAc) microspheres o...

Figure 3.21

Confocal laser scanning microscopy

(

CLSM

) images of P(NIPAM‐

co

‐A...

Figure 3.22 SEM photographs of chitosan microspheres prepared by membrane em...

Figure 3.23 CLSM images of (a) SRCG microspheres excited at 365 nm, (b) C–G ...

Figure 3.24 Schematic representation of BSA (green dots) loading patterns in...

Figure 3.25 Conceptual illustration of preparation procedures for chitosan m...

Figure 3.26

Transmission electron microscope

(

TEM

) micrographs of chitosan m...

Figure 3.27 SEM of chitosan microparticles with different molecular weights....

Figure 3.28 Preparation process of HTCC microspheres by combining thermogela...

Figure 3.29 The microphotograph (a) and SEM image (b) of HTCC microspheres. ...

Figure 3.30 CLSM images of FITC‐BSA loaded HTCC microspheres suspended in PB...

Figure 3.31 The optical microscopic photographs of agarose beads: (a) prepar...

Figure 3.32 Size distribution of agarose beads prepared by membrane emulsifi...

Figure 3.33 Optical micrographs of emulsion droplets prepared by using diffe...

Figure 3.34 The interfacial tension between different oil phase and water ph...

Figure 3.35 (a) Schematic diagram of the home‐designed large‐scale membrane ...

Figure 3.36 Optical micrographs of (a) homemade agarose microspheres, (b) Se...

Figure 3.37 Optical micrographs (a), (b), and (c) were 6% agarose/6% dextran...

Figure 3.38 AFM images of (a) the surface and (b) the inner part of polysacc...

Figure 3.39 A schematic representation of the preparation process of blank a...

Figure 3.40 Characterization results of blank alginate–chitosan microspheres...

Figure 3.41 Effects of emulsifier ratios on microsphere's morphology. (a)

V

S

...

Figure 3.42 (a) Schematic representation of the continuous membrane emulsifi...

Figure 3.43 Experimental apparatus of the rotating membrane emulsification. ...

Figure 3.44 Microscopic photographs of KGM microspheres prepared under the o...

Figure 3.45 SEM's of dry cross‐linked particles. (a) PVA microsphere and (b)...

Figure 3.46 PVA liquid droplets formation by pulsed back‐and‐forward membran...

Figure 3.47 (a) Schematic illustration of fabrication of hHb–HSA microsphere...

Chapter 4

Figure 4.1 Formation of double emulsion using direct membrane emulsification...

Figure 4.2 Optical micrographs of lipiodol W/O/W double emulsion prepared by...

Figure 4.3 The size distributions of lipiodol double emulsion prepared by di...

Figure 4.4 Micrographs of W/O/W double emulsion obtained by (a) direct membr...

Figure 4.5 Size distributions of PLA microcapsules prepared by direct membra...

Figure 4.6 (a–c) SEM photographs of PLA microcapsules prepared by combining ...

Figure 4.7 (a, b) Effect of PVA concentration in the outer aqueous phase on ...

Figure 4.8 SEM photographs of PLA microcapsules prepared by membrane with di...

Figure 4.9 Relationship between the mean size of PLA microcapsules and the p...

Figure 4.10 Effect of (a) PLA/PLGA ratio and (b) NaCl concentration in outer...

Figure 4.11 (a) Effect of the inner aqueous phase volume on the drug cumulat...

Figure 4.12 Effect of (a) NaCl concentration in outer aqueous phase, (b) rhI...

Figure 4.13 (a) Preparation diagram of SLMCs using the direct membrane emuls...

Figure 4.14 Images of W/O/W double emulsion with different concentrations of...

Figure 4.15 SEM photographs of multicore microcapsules produced with (a, b) ...

Figure 4.16 Schematic illustration showing the preparation of QD‐encoded com...

Figure 4.17 OM and SEM photographs of composite microspheres showing effect ...

Figure 4.18 SEM photographs of composite particles showing effect of PVP amo...

Figure 4.19 (a) Typical OM photograph of W/O/W double emulsion prepared by t...

Chapter 5

Figure 5.1 Rapid membrane emulsification process (left) and the as‐prepared ...

Figure 5.2 SEM photographs of PLA nanoparticles. Source: Wei et al. [5]/Else...

Figure 5.3 SEM images of PLGA microspheres with –OH (a); –COOH (b); and –COO...

Figure 5.4 SEM images of PST particles with monomer/n‐hexadecane ratio of 1 ...

Figure 5.5 CLSM images of FITC‐HBsAg adsorbed on different PLA microspheres:...

Figure 5.6 The scheme and SEM images of DP (particles with cationic DDAB mod...

Figure 5.7 A scheme of preparing the ropivacaine‐loaded PLGA microspheres vi...

Figure 5.8 The serum biochemical analysis on the cardiotoxicity of different...

Figure 5.9 Schematic illustration of micronsized polydopamine microcapsule b...

Figure 5.10 The uptake profile of chitosan particles by

antigen presenting c

...

Figure 5.11 CLSM (a) and SEM (b) images of quaternized chitosan MGels with d...

Figure 5.12 CLSM images (a) and the size distributions (b) of microspheres p...

Figure 5.13 Optical micrographs of agarose beads prepared by rapid/premix ME...

Figure 5.14 The scheme of surface chemical structure (a) and SEM images (b) ...

Figure 5.15 Schematic diagram of the preparation of colloidosomes by combini...

Figure 5.16 Microscopic photographs of KGM emulsions prepared with different...

Figure 5.17 Confocal laser scanning microscope (a–b) and flow cytometer anal...

Figure 5.18 SEM images (up) of the microspheres and corresponding schematic ...

Figure 5.19 The scheme of the preparation of uniform‐sized exenatide‐loaded ...

Figure 5.20 Characteristics and

in vitro

antigen release behavior of pH‐resp...

Figure 5.21 A schematic process of preparing single‐core PLGA microcapsules ...

Figure 5.22 Fabrication of double‐emulsion‐templated porous microspheres by ...

Figure 5.23 (a)–(c) Effect of membrane pore size on the particle size of mic...

Figure 5.24 Schematic diagram and images of the rod‐shaped polymer particles...

Figure 5.25 SEM photos of PLGA particles prepared at pH (a) 5.7, (b) 6.5, (c...

Figure 5.26 SEM photos of PLGA particles prepared at different stirring rate...

Figure 5.27 The characteristics and the

in vitro/vivo

performance of HTCC‐NP...

Figure 5.28 The conjugation strategy and characterizations of RGD–PEG–CNP:PT...

Figure 5.29 The characteristics and

ex vivo

performance of HNP:siRNA. (a) Th...

Figure 5.30 Schematic depicting the erythrocyte‐membrane‐camouflaged program...

Chapter 6

Figure 6.1 Timeline (1966–1986) indicating crucial scientific breakthrough o...

Figure 6.2 Molecular monomers

D

‐(−)‐lactic acid and

L

‐(+)‐lactic acid of the...

Figure 6.3 Structure of PLGA (

x

is the number of lactic acid units and

y

is ...

Figure 6.4 Hydrolysis of PLGA molecules.

Figure 6.5 Effect of the emulsifier concentration in the oil phase on the dr...

Figure 6.6 Effect of different additives on drug encapsulation efficiency. S...

Figure 6.7 Schematic illustration of the coalescence process between inner d...

Figure 6.8 Diagram of frequency (red line) and dissipation (black line) vs. ...

Figure 6.9 AFM images of PLGA films: before adsorption: (a

1

) PLGA‐OH, (b

1

) P...

Figure 6.10 SEM photographs of microspheres prepared by different solidifica...

Figure 6.11 The schematic diagrams of microspheres formation process for dif...

Figure 6.12 Schematic diagram of the preparation of ropivacaine hydrochlorid...

Figure 6.13 The result of a sensory nerve block test: the dotted line is the...

Figure 6.14 Impact of additives in the inner aqueous phase on the bioactivit...

Figure 6.15 The schematic diagram for the mechanism of acylation inhibition ...

Figure 6.16 Quantification of acylated exenatide in PLGA microspheres vs. ti...

Figure 6.17 (a) Size exclusion chromatography (SEC‐HPLC) of rhGH after recov...

Figure 6.18 CLSM images of pH‐sensitive dye‐loaded PELA‐1 (a

1

–a

7

), PELA‐2 (b

Figure 6.19 The weight gains in hypophysectomized rats treated with rhGH sol...

Figure 6.20 Active recovery of lysozyme in the PLA/PLGA microsphere/microcap...

Figure 6.21 Structure of chitosan.

Figure 6.22 The DDA classification standard of chitosan.

Figure 6.23 The schematic explanation for chitosan microspheres formation by...

Figure 6.24 Effect of the crosslinking method on the IA loading content. Sou...

Figure 6.25 IA release profiles from CG (pink), CH40 (green), and CH80 (blac...

Figure 6.26 Insulin activity retention was obtained with different preparati...

Figure 6.27 Cumulative release of insulin and corresponding LSCM images of i...

Figure 6.28

In vitro

BSA (a) loading efficiency and (b) release profiles mea...

Figure 6.29 The integrity of insulin released from chitosan microspheres by ...

Figure 6.30 The effect of insulin‐loading methods on

in vitro

release profil...

Figure 6.31 (a) Blood glucose levels of diabetic rats after an oral administ...

Figure 6.32 Optical microscopic photo of uniform chitosan W/O emulsion (a), ...

Figure 6.33 The

in vitro

release profile of insulin in simulated gastric flu...

Figure 6.34 The serum glucose concentration after oral administration of ins...

Chapter 7

Figure 7.1 iRGD‐conjugated PTX nanoparticles/nanodots and their disparate pe...

Figure 7.2 Cellular uptake and intracellular distribution of NPs with differ...

Figure 7.3 (a) The structure diagram of HNP:siRNA. (b)

Confocal laser scanni

...

Figure 7.4 (a) Schematic diagrams of the arrangement pattern of different po...

Figure 7.5 Cellular internalization of GO in macrophages and nonphagocytic c...

Figure 7.6 (A) Image illustrating the superstructure integrating GO inside t...

Figure 7.7 (a) Schematic illustration of As@Fn nanomedicine and the specific...

Figure 7.8 (a) SEM image of uniform particle size of HP‐a. (b) SEM image of ...

Figure 7.9 (a) Schematic illustration of the preparation of the Fn@CaP nanop...

Figure 7.10 Schematic representation of cross‐linked nanocapsules before and...

Figure 7.11 Schematic illustration of HM/S/MC with efficient HIF‐1 siRNA del...

Figure 7.12 Schematic representation showing the main components of Dox@MOF‐...

Figure 7.13 Schematic illustration of CNPs‐loaded hemosomes for programmed c...

Figure 7.14 Schematic illustration of the MRI‐guided targeting dual‐responsi...

Figure 7.15 Schematic illustration of the construction of NIR‐triggered nano...

Figure 7.16 Target principal scheme of PNIPAM‐based thermal targeting antica...

Figure 7.17 Illustration of endogenous nanosonosensitizers for focused US‐au...

Figure 7.18 Schematic illustration of UCNP‐based RM‐coated dual‐targeted bio...

Figure 7.19 Schematic illustrating cancer cell membrane‐coated HCPT nanocrys...

Chapter 8

Figure 8.1 Evolution of vaccine adjuvant and delivery system.

Figure 8.2 “Plug and play” platforms for vaccine assembly and delivery.

Figure 8.3 Modularizing strategies for the assembly of particulate vaccine....

Figure 8.4 Cationic

polymer/lipid nanoparticles

(

PLNPs

) formed an antigen de...

Figure 8.5 DBs of various shapes showed different endocytosis efficiencies. ...

Figure 8.6 (a) Alum‐stabilized Pickering emulsion allowed for the improved h...

Figure 8.7 TEM images of the internalization of 350 nm GO (above, a–d) and 2...

Figure 8.8 Exploiting the softness of Pickering emulsion for the enhanced va...

Figure 8.9 Particulate vaccines to enhance the distribution, internalization...

Figure 8.10 Deformable Pickering emulsion to potential the LN accumulation o...

Figure 8.11 Spatiotemporal delivery of nanovaccines for tumor immunotherapy....

Figure 8.12 Strategy of using self‐healing microcapsules to modulate immuniz...

Figure 8.13 Gas generating strategy for cytosolic delivery (a) Schematic dia...

Figure 8.14 TEM images and the corresponding scheme illustrating lysosome es...

Chapter 9

Figure 9.1 The role of uniform microspheres and super‐porous microspheres in...

Figure 9.2 Scheme of the effects of particle size uniformity on separation e...

Figure 9.3 The structural formula of agarose.

Figure 9.4

Scanning electron microscopy

(

SEM

) photographs of agarose microsp...

Figure 9.5 Optical microscopic photographs of agarose microspheres prepared ...

Figure 9.6 Optical microscopic photographs of agarose microspheres prepared ...

Figure 9.7 Comparison of pressure‐flow rate curves of three kinds of agarose...

Figure 9.8 (a) Chromatogram of model proteins, (b)

K

d

‐

R

m

curves, and (c) por...

Figure 9.9 (a) Chromatogram of model proteins, (b)

K

d

‐

R

m

curves, and (c) por...

Figure 9.10 The structural formula of KGM.

Figure 9.11 Size distribution of KGM microspheres prepared by rapid membrane...

Figure 9.12 (a) Optical micrograph of KGM microspheres; (b) SEM of KGM micro...

Figure 9.13 The desalting effect of filamentous hemagglutinin on Sephadex G2...

Figure 9.14 Stability of KGM gels measured as change in the recovery of prot...

Figure 9.15 SEM images of PST before and after modification (A1, A2 before; ...

Figure 9.16 AFM images of PST before and after modification (A1, A2 before; ...

Figure 9.17 Separation of exenatide from peptide crudes using PST‐based anio...

Figure 9.18 MS spectra of synthetic crude peptides (orange) and purified exe...

Figure 9.19 Three‐step profiles of liquid chromatography purification of oct...

Figure 9.20 The ESI–MS of purified octreotide. Source: From Zhang et al. [26...

Figure 9.21 The spectra of

1

H NMR: (a) purified octreotide by PST column, (b...

Figure 9.22 HPLC of nitrilotriacetic acid using the direct method on PST col...

Figure 9.23 The relationship between the eluent flow‐rate and the column pre...

Figure 9.24 The profile of chromatographic purification of icariin from crud...

Figure 9.25 HPLC analysis of chromatographic fractions corresponding to peak...

Figure 9.26 Chromatograms of phenol and its derivatives obtained by differen...

Figure 9.27 Chromatograms of four standard peptides obtained by different pa...

Figure 9.28 Peptide selectivity of PDVB (25 μm) vs. batch number for four co...

Figure 9.29 Chromatogram and electrophoresis of kallikrein purified on PGMA–...

Figure 9.30 Chromatogram of kallikrein purified on Octyl Sepharose FF (15% a...

Figure 9.31 Recovery of refolding lysozyme with dilution or HIC. 1. dilution...

Figure 9.32 SEM image of PHEMA microspheres used as chromatographic packing ...

Figure 9.33 Chromatograms of icariin isolated from the extract solution of

E

...

Figure 9.34 HPLC analysis of the crude extract solution and the target peak ...

Figure 9.35 Protein separation performance of smooth and golf ball‐like sili...

Figure 9.36 UV spectrum of the mixture of BSA and BHb before (a) and after (...

Figure 9.37 Electrophoresis of the mixture of BSA and BHb before (a) and aft...

Figure 9.38 Schematic image of super‐porous microspheres. Source: Gu et al. ...

Figure 9.39 SEM photographs of POROS R1 particles. Source: Gu et al. [38]/El...

Figure 9.40 Schematic mechanism of the formation of super‐pores in polymeric...

Figure 9.41 Effect of amount of Span 80 on the morphology of microspheres (T...

Figure 9.42 Pore size distribution curve of the microspheres prepared by 40%...

Figure 9.43 Effect of the co‐operation of surfactant and diluents on the mor...

Figure 9.44 Effect of mixed surfactants on the morphology of the highly cros...

Figure 9.45 Two‐step method to prepare the aqueous two‐phase system (ATPS). ...

Figure 9.46 The schematic photographs of boundary loss (a) and boundary rebu...

Figure 9.47 Well‐dispersed super‐porous microspheres prepared by combining t...

Figure 9.48 Adsorption isotherms of BSA on super‐porous PST microspheres bef...

Figure 9.49 Preparation of cross‐linked PVA hydrogel‐coated super‐porous PST...

Figure 9.50 Chemical reaction between dextran and P(GMA‐DVB) microspheres at...

Figure 9.51 Relationship between the column backpressure and flow velocity. ...

Figure 9.52 Column efficiency versus flow velocity. Column, 100 × 4.6 mm I.D...

Figure 9.53 Experimental and simulated uptake curves of HB‐VLPs (c0 = 0.12 m...

Figure 9.54 Effect of loading quantities (0.5, 1.0, 1.5, and 2.0 mg protein ...

Figure 9.55 (a) HPSEC assay of HB‐VLPs eluted by 1.0 M NaCl in 20 mM sodium ...

Figure 9.56 Schematic demonstration of HB‐VLPs adsorption and disassembly du...

Figure 9.57 Morphology of Vero cell line grown on (a) A‐KGM‐1225 (b) Cytodex...

Figure 9.58 Effect of KGM microcarriers rigidity on MSCs proliferation. (a) ...

Figure 9.59 Comparation of cell proliferation between 12%‐KGM microcarriers ...

Figure 9.60 Optical micrographs of agarose microspheres encapsulating cells ...

Figure 9.61 Distinctive light‐scattering signatures of dot plot data of agar...

Chapter 10

Figure 10.1 Cross‐flow membrane emulsification method. Source: From Hu et al...

Figure 10.2 Process flow diagram of high throughput membrane emulsification ...

Figure 10.3 Magnification verification of effective membrane area.

Figure 10.4 A series of novel cross‐flow membrane emulsification equipment [...

Figure 10.5 Premix membrane emulsification method.

Figure 10.6 Disruption of coarse emulsion by microporous membrane.

Figure 10.7 Process flow diagram of premix membrane emulsification equipment...

Figure 10.8 A series of novel premix membrane emulsification equipment [1–3]...

Figure 10.9 Principle of rotary membrane emulsification equipment. (1) Rotar...

Figure 10.10 Process flow diagram of rotary membrane emulsification equipmen...

Figure 10.11 A series of novel rotary membrane emulsification equipment.

Figure 10.12 GMP production platform for sustained release microspheres by m...

Figure 10.13 SEM micrographs (a–c) and size distributions (d) of three batch...

Guide

Cover Page

Title Page

Copyright

Co‐Authors

Preface

Table of Contents

Begin Reading

Index

Wiley End User License Agreement

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Novel Membrane Emulsification

Principles, Preparation, Processes, and Bioapplications

Guanghui Ma

Author

Prof. Guanghui Ma

Institiute of Process Engineering Chinese Academy of Sciences

1 Beierjie, Zhongguan Cun

Haidian District

Beijing

China, 100190

Cover Image: © Guanghui Ma

All books published by WILEY‐VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.

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© 2023 WILEY‐VCH GmbH, Boschstraße 12, 69469 Weinheim, Germany

All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law.

Print ISBN: 978‐3‐527‐34881‐7

ePDF ISBN: 978‐3‐527‐83083‐1

ePub ISBN: 978‐3‐527‐83084‐8

oBook ISBN: 978‐3‐527‐83085‐5

Co‐Authors

Dongxia Hao

Jie Wu

Fangling Gong

Wei Wei

Yufei Xia

Hua Yue

Yi Wei

Weiqing Zhou

Lan Zhao

Xiangming Na

Yanlin Lv

Nan Wu

Yuning Hu

State Key Laboratory of Biochemical Engineering

Institute of Process Engineering

Chinese Academy of Sciences

Preface

Polymer microspheres and microcapsules have supported the revolutionary development of industry and led to the successful applications of various new techniques. In pharmaceutical and biomedical fields, for example, the dextran microsphere enabled mammalian cell culture in a large bioreactor, which promoted the development of vaccines such as the COVID‐19 vaccine and the rabies vaccine. The crosslinked rigid agarose microsphere has enabled the successful scale‐up of chromatographic separation and purification of pharmaceutical proteins and vaccines and led the rapid development of biopharmaceutical industry. Polylactide microsphere and microcapsule promoted the development of sustained release formulation of peptide drugs, which changed daily injections to weekly, monthly, and even yearly, improving the life quality of patients apparently.

The size distribution of microspheres is crucial for bio‐applications. For example, uniform agarose microsphere can increase the separation resolution, and impurities can be removed from products by fewer steps. Uniform polylactide microcapsules can release the drug constantly, compared with non‐uniform particles, and can guarantee the reproducibility of the products. Especially for targeting drug delivery, the size decides the particle distribution in the body; non‐uniform particle will result in lower bioavailability and higher side effects because the particle diameter is one of the key factors that control the pharmacokinetics and efficacy of a loaded drug.

Polymer microspheres/microcapsules can be prepared from monomers or preformed polymers. The former includes emulsion/soap‐free emulsion polymerization, disperse/precipitate polymerization, microemulsion polymerization, mini‐emulsion polymerization, suspension polymerization, and seeded polymerization. By emulsion/soap‐free emulsion polymerization and disperse/precipitate polymerization, uniform microspheres with submicron and micron sizes, respectively, can be prepared easily; however, the encapsulation of active components and morphology control are difficult due to their particulate mechanisms. On the other hand, suspension polymerization can encapsulate active components easily, but the size control is difficult and the size distribution is very broad.

The microspheres/microcapsules also can be prepared by using preformed polymer including natural polymer (agarose, etc.) and synthetic polymer (polylactide, etc.) as the materials. Especially for biomedical applications, preformed biocompatible polymers are usually used to prepare microspheres and microcapsules. Most often used method is the emulsion‐solidification method, similar to the above suspension polymerization method. That is, the emulsion is prepared first, and the droplets are solidified into microspheres. Although the active components can be encapsulated easily, the size control is difficult and the size distribution is very broad, which is unfavorite to reproducible industrialization.

Membrane emulsification technique (MET) solved this problem. The uniform droplets can be formed by using monomers or preformed polymer solutions as the dispersed phases. As a result, uniform microspheres can be obtained by polymerizing monomers or solidifying the droplets. Furthermore, the active components can also be encapsulated if they are added to the monomers or preformed polymer solutions before emulsification.

Membrane emulsification has the following advantages, which has been recognized until now:

Uniform droplets can be prepared, so the sizes of droplets and particles solidified from droplets are easy to control by changing the pore sizes of membranes, and the reproducibility is excellent;

W/O, O/W, and W/O/W or O/W/O emulsions have been successfully prepared by controlling the preparation conditions, including interfacial tension of dispersed phase and membrane, transmembrane pressure, flow rate of continuous phase, and so forth. Therefore, hydrophobic, hydrophilic, and composite microspheres and microcapsules can be prepared, respectively, from different emulsion types;

The preparation condition is mild without violent mechanical stirring, so the temperature‐sensitive components can be encapsulated without losing their bioactivity;

The coalescence and breakup of droplets during solidification can be avoided, resulting in high stability of the emulsion and high encapsulation efficiency of the microcapsules;

Scale‐up is easy in principle because the productivity can be amplified by increasing membrane area;

Because the size is uniform, the effect of the size and morphology of microspheres on application results can be studied systematically and quantitatively, and the optimum size can be selected to obtain the best application results.

However, the MET, especially the direct membrane emulsification process, has the following difficulties to be solved for industrialization:

The preparation condition to obtain uniform droplets has to be optimized for different systems; it needs a huge amount of trial‐and‐error experiments;

The interfacial tension between the dispersed phase and the membrane should be high, which is unfavorite for polar monomer systems such as hydroxyethyl methacrylate (HEMA);

The control of trans‐membrane pressure should be carried out carefully in a narrow window; otherwise, the size distribution will become broader;

The dispersed phase with high viscosity is hard to be emulsified into continuous phase to obtain uniform droplets with high productivity;

If one membrane has a crack, the whole production will fail. And, how to produce pharmaceutical microspheres in the

good manufacturing practice of medical products

(

GMP

) is also a big challenge;

The druggability of microcapsules produced by this technique needs to be verified.

In order to overcome these difficulties, we studied systematically from fundamental research to equipment development and industrialization. We developed the mathematical model to predict the experimental conditions (transmembrane pressure, flow rate of continuous phase, etc.) to obtain uniform droplets and particles for different systems with different physicochemical properties (viscosity of dispersed phase, emulsifier type, interfacial tension, etc.) and successfully developed MET process from O/W, W/O, and double emulsion systems. We also developed rapid MET instead of direct MET to prepare smaller particles, especially for viscous systems. In addition, we developed various morphologies of microspheres by using uniform droplets as templates. Furthermore, the applications and their advantages in sustained release formulation of drugs, targeting delivery of anticancer agents, vaccine delivery, and biochemical engineering (cell culture and bio‐separation) were studied. In these application studies, it has been proved that the uniform size has superior advantages. In order to industrialize MET, we have designed equipment and GMP production line of uniform microspheres, and some of these products have been approved for clinical trials. It will be expected that more and more products of uniform microspheres by using MET will be industrialized and put on the market. These contents will be introduced in the following chapters.

With the development of science and technology and the need to improve human life quality, more and more uniform microspheres and microcapsules should be designed and used in the biomedical/pharmaceutical fields, and this technique should be extended to more and more systems besides polymer systems to obtain such things as uniform silica gel particle, inorganic particles, and various composite particles for different emerging applications. Furthermore, preparing more smaller particles with several tens of nanometers by MET which are important in targeting drug delivery and mRNA delivery, is still a big challenge in the future.

Membrane has been widely used for filtration in many fields. But in the last 30 years, this hidden talent of membranes for emulsification has been found. We can use MET to prepare uniform emulsions and uniform particles (microspheres and microcapsules) from both monomer and preformed polymer systems, which have never been realized by conventional chemical engineering processes. This new process is becoming universal through a huge amount of R&D work and has been extended to many application fields, especially in bio‐applications.

We hope this new process will benefit more researchers in institutes and industries. Furthermore, microspheres/microcapsules used in biomedical area are attracting new attention, such as in vaccine delivery, especially for infectious disease vaccines and personalized tumor therapeutic vaccines. Uniform microspheres have taken and will take very important role in this area.

Therefore, we summarized the advance of MET from principle to practice and applications, which mainly consisted of our research work on MET. We believe this book will benefit the researchers and graduate students in chemical engineering, biomedical and biological engineering, and polymer materials from academia and industry.

Our research achievements in this book were supported and contributed by National Natural Science Foundation of China, Ministry of Science and Technology of China, the Chinese Academy of Sciences, and all colleagues and students in our team, as well as collaborators. I would like to thank their support and cooperation sincerely.

Guanghui MaProfessor and Director of State Key Laboratory of Biochemical Engineering,Institute of Process Engineering, Chinese Academy of Sciences.

1Membrane Emulsification Process: Principle and Model

1.1 Introduction

Emulsions or particles prepared from emulsion with size‐uniformity and size‐controllability present distinctive advantages in industrial applications, such as microcapsules in drug delivery, particulate adjuvants for vaccination, and microspheres media in chromatographic separation and cell culture [1–4]. The early techniques of large‐scale producing emulsion mostly depend on externally exerting strong dissipated energy into fluid mixtures, such as the rotor–stator, the high‐pressure homogenizers, and the ultrasonic emulsification systems, in which the dissipated energy cannot be controlled homogeneously and the emulsion with broad size‐distribution is often obtained. In recent decades, a great amount of work begins to explore the devices with milder and more controllable dissipating techniques to produce more uniform emulsion. Among the emerging devices, membrane emulsification technology (MET) has been addressed as a widely concerned group of uniform emulsification techniques, during which the to‐be dispersed phase could grow into uniform droplets at uniform membrane pores with help of gentle and accurately controlled driving force [5]. Due to the controllability of droplet size by uniform membrane pore instead of the turbulent shearing flow, MET offers many advantages not only in narrow size distribution of droplets but also in lower energy requirement and suitability for emulsification of shear or temperature sensitive components.

According to different principles of emulsion preparation, the MET can be divided into two groups, the cross‐flow membrane emulsification [6] and the premix membrane emulsification [7], also called as direct membrane emulsification and rapid membrane emulsification. The cross‐flow MET is a process of two liquid phase flow. The to‐be dispersed phase is pressed through the membrane's inner channel by pressure, generates the droplets at the membrane pores, and then the droplets until to a certain size are carried away by continuous phase fluid, as shown in Figure 1.1a. There are certain similarities existing between droplet breakup in premix and cross‐flow emulsification depending upon the operating parameters. Comparatively, premix emulsification begins with a coarse emulsion, and then is extruded and homogenized through a porous membrane under a higher pressure to obtain fine emulsion, as shown in Figure 1.1b. Although the size of the droplets is not as monodisperse as abovementioned cross‐flow emulsification, premix emulsification is still an efficient route to produce emulsions with high dispersed‐phase fraction.

Figure 1.1 Two basic forms of membrane emulsification. (a) Cross‐flow MET. (b) Premix MET.

The processing parameters of MET controlling emulsion droplet size and distribution have been extensively analyzed both experimentally and theoretically in these years [8–10]. A large number of empirical laws were discovered and a series of microscopic models were established by physics and mathematics language. Here, we would introduce the representative mechanisms of both cross‐flow MET and premix MET and their developments over the years from macro to micro scales.

1.2 Cross‐Flow Membrane Emulsification

During cross‐flow MET, various parameters from different magnitudes would exert combined actions, including the interfacial surface property (diffusion, surface tension, and viscosity of two phases) and the macroscopic operation conditions (disperse phase velocity or pressure and continuous phase velocity) [6]. Generally, the droplet size was experimentally controlled primarily by the choice of membrane, the cross‐flow velocity, and the transmembrane pressure. Typically, a factor of 2–6, depending on the properties of dispersed phase and continuous phase and even the structure of membrane is found between pore size and droplet size. Accordingly, the built numerical methodologies also aimed to describe the formation of droplet and predict the droplet size and the size distribution, such as the force and torque balances [11–13], surface free‐energy minimization [14, 15], computation fluidic dynamics (CFD) [16], Lattice Boltzmann [17] and phase flow method [18], and so forth. These microscopic descriptions significantly facilitated the prediction of manufacturing throughput of emulsion and particle, optimization of MET operation, and design and scale‐up of emulsion modules from laboratory to industrial production. The representative mechanisms and models involving cross‐flow MET are intensively discussed as follows.

1.2.1 Mechanism of Droplet Formation

It has been observed that the uniformity of final emulsion mainly depends on the droplet formation behavior in membrane emulsification, except the cases of the emulsion polydispersity caused by instability of the emulsion and wettability of the dispersed phase. Two mechanisms of droplet detachment behavior affecting size distribution were observed in cross‐flow MET, i.e. the shear‐induced droplet formation (SHE) and the spontaneous transformation‐based () droplet formation [19, 20]. The SHE mechanism describes the situation where droplet is detached by uneven shear force from cross‐flow or rotary flow of continuous phase. The STB mechanism describes the situation where the droplet breaks off without any additional shearing and just by the variation of interfacial free energy. Droplet detachment driven by mechanism of STB at elongated outlet would result in more uniform emulsion than that driven by mechanism of SHE at circular outlet [21–23]. The Shirasu porous glass (SPG) membrane with a pore geometry composed of tortuous ellipsoidal cylinders has characteristics between circular and elongated outlets. Consequently, both mechanisms were observed via microscope visualization by tailoring the emulsification environments [19].

Here, we compared three typical emulsification environments, respectively, the anionic emulsifier (sodium dodecyl sulfate [SDS]), the nonionic stabilizer (polyvinyl alcohol [PVA]), and the cationic emulsifiers (acetyl trimethyl ammonium bromide [CTAB]) in water continuous phases. Meanwhile, the divinylbenzene was selected as the dispersed phase in O/W emulsion droplet. Figure 1.2 captures a typical spontaneous formation of droplet in continuous phase of 0.2% wt SDS solution. The droplet, respectively, experienced the growth, the staying and the detaching stages. Obviously, the staying stage lasts for the longest time and acted as the speed‐limited step in droplet spontaneous formation and detachment.

This spontaneous behavior happened specifically at emulsifiers of nonionic PVA and anionic SDS at high concentrations of emulsifiers. As shown in Figure 1.3a, b, a droplet labeled with the fuzzy circles and arrows is moving out from the pore. Comparatively, the growing droplets tend to adhere to pores and refuse to detach in other emulsification environments, such as pure water and solutions, respectively, of CTAB ≥ 0.05% wt, low concentration of PVA &lt; 0.5% wt, and SDS &lt; 0.04% wt. These adhering droplets at adjacent pores tend to coalesce into larger droplets as shown in Figure 1.3c, d, and have to be pulled out at a higher pressure or a strong shearing by continuous phase flow, and finally formed a polydispersed emulsion.

Figure 1.2 Growth of droplets on surface of SPG membrane.

Figure 1.3 Droplets' spontaneous detaching and adhering behaviors.

Because the interfacial tension between dispersed phase and continuous phase act as the major adhesion force on droplet, we further investigated the relationship between interfacial tension and droplet detachment behaviors. Figures 1.4 and 1.5 showed that the higher interfacial tension, such as in the case of PVA with concentration below 0.5%, would result in droplets adhesion and final polydispersed emulsion. However, if the interfacial tension could be decreased effectively to the lowest, such as in solution of SDS above 0.2%, the droplet would demonstrate an obvious spontaneous detachment and the uniform emulsion would form finally as shown in Figures 1.6 and 1.7. It can be speculated that the droplet's spontaneous detachments could effectively avoid the coalescence between droplets and nonuniform shearing field from continuous phase flow, and finally form uniform emulsion as shown in Figures 1.6 and 1.7. Comparatively, SDS showed stronger ability to decrease interfacial tension and presented more significant tendency of spontaneous detachment, and could prepare more uniform droplets. It confirmed again that the spontaneous formation behavior of droplets would facilitate uniform emulsion formation.

Figure 1.4 Droplets distributions at different PVA concentrations.

Figure 1.5 Interfacial tension of oil–water phase at different PVA concentrations.

Figure 1.6 Droplets distributions at different SDS concentrations.

Figure 1.7 Droplets distributions at different SDS concentrations.

1.2.2 Force Balance Model

The force balance model are the most universal explanation for various experimental phenomena and laws during membrane emulsification [12, 24]. The description of individual droplet formation and detachment by forces is very intuitive and easily understood. As shown in Figure 1.8, it focuses on analysis of microscopic forces on droplet at moment of droplet gushing out from membrane pores, including the shear force Fcf, the buoyancy force FB, the interfacial tension force Fγ, and the static pressure difference force Fsp.

Specifically, the interfacial tension force,

(1.1)

represents the effects of dispersed‐phase adhesion on pore opening as the retaining force for adhesion.

The static pressure difference force Fsp is the force caused by pressure difference between the dispersed phase and the continuous phase at membrane surface. In quasi‐static state, it is described as as follows:

(1.2)

where Ap is the cross‐sectional area of the droplet neck at pore and here approximately assumed as area of pore, and ddr is the dynamic droplet diameter, which is increasing until droplet detaches from pore.

The cross‐flow drag force, Fcf, is created by the continuous phase flowing past the droplet parallel to membrane surface [25]. According to Stokes' equation in a simple shear flow and assuming that the droplets are formed in laminar sublayer, it is described as as follows:

(1.3)

The dynamic lift force, Fdl, results from the asymmetric velocity profile of the continuous phase near droplet and is defined as follows:

(1.4)

in which, shearing force τw is controlled by the continuous phase velocity uc[22] and is deduced based on the definition of Fanning friction factor as given below:

(1.5)

Figure 1.8 Force analysis of droplets on outlet of membrane pore.

where ρc is the density of continuous phase, uc is the flow velocity of continuous phase, and f is a dimensionless factor defined by the Reynolds number Re as follows:

(1.6)

where Re = ρcucD/μc, D is the inner diameter of the cross‐flow channel (membrane channel), and μc is the viscosity of continuous phase.

If the density of dispersed phase cannot be neglected, the buoyancy force FB of a droplet with volume Vd should be amended as the resultant force FBG of buoyancy and gravity FG, and described as the density difference between two phases.

(1.7)

The linear momentum force Fm is caused by flow movement of a mass of dispersed phase out from the pore outlet.

(1.8)

Among these forces, Fγ is the holding force to make droplets adhere at membrane pore outlet, while Fdl, FBG, Fm, and Fcf are the detaching forces to drive droplets away from pores, and the inertia forces Fm and buoyancy forces FBG can be neglected when they are approximately from six to eight orders of magnitude smaller than other forces after calculation. If the total adhesion forces are greater than the detaching force, the droplet would continue to grow on outlet of membrane pore. If the adhesion forces are less than the detaching forces, the balance of forces on the droplet is lost, and the droplet begins to deform, elongate, form a neck, detach from the membrane pore, and finally enter the continuous phase. The contributions of various forces depended on droplet size. For smaller micron‐size pores, the inertial and buoyancy forces are much smaller than the viscous drag force and surface tension, respectively, and thus can be ignored in balance model; otherwise, they will play vital role for large droplets with hundreds of microns.

The prototype of force balance model was first put forward by Peng and Williams in 1998 [26]. They predicted the size of droplet generated from the capillary with inner diameter of 45 microns and considered that the droplet surface was mainly affected by forces, including the flow drag force (Fcf, generated by the continuous phase shearing action parallel to membrane surface), the buoyancy force (FB, generated by the density difference between two phases), and Fγ (represents the force generated by the interfacial tension). Three forces get balanced as Fcf + FB = Fγ. Schroder and Wang supplemented this microscopic forces model with more accurate descriptions, including the static pressure difference force (FSP, generated from the pressure difference between the continuous phase inside and outside the droplet), the dynamic lift force (Fdl, generated from the asymmetric velocity distribution profile of continuous phase near the droplet), and the inertial force (Fm, related to the momentum of fluid movement flowing out of the membrane orifice) [27, 28]. Further, Xu et al. introduced variables of continuous phase flow velocity in force balance model and attempted to predict the change rule of emulsion droplet size under different continuous phase velocities [29]. They found that the force balance model agreed well with the experimental data. The droplet size and droplet formation time decreased with increase of continuous phase flow rate. Since their emulsification experiment was completed in continuous phase without emulsifier and the droplet size was obtained from microscope observation at membrane pore, the equipment and environment of their prediction were still quite different from the actual membrane emulsification. In addition, the dynamic oil–water interfacial tension of droplet surfaces and the influence of operating conditions of dispersed phase on emulsification process were not considered in both of their experiments and model.

Later, G. De Luca et al. introduced more variables, including the dispersed phase transmembrane pressure and the dynamic interfacial tension into abovementioned force balance model. The coupling effect of these variables on the droplet size was investigated [11]. They found that if droplet formed earlier than the interfacial tension arriving at equilibrium, the droplet size was directly proportional to the transmembrane pressure. Conversely, it was not related to the transmembrane pressure. They developed a modified balance model from another perspective of contact line [30]. It is assumed that the film surface exists as long as the force arrives in balance near the contact line; the droplet will adhere to the edge of membrane pore in an inclined position and deform until it finally detach from pore. In the force balance formula based on the contact line, all the forward contact angles, backward contact angles, and the minimum and maximum volume of droplet growth could be calculated (Figure 1.9). The validation of this model is completed under different conditions, including continuous phase velocity, membrane pore size, and interfacial tension. The linear relationship between droplet size and membrane pore size and the change of interfacial tension during droplet formation are all predicted.

1.2.3 Torque Balance Model

Above mentioned force balance models define the generated droplet as a point and the droplet will peel off immediately after two groups forces arriving balance, while the torque model regards the droplet as a sphere, and the droplet will rotate and escape from membrane pore until torques on droplet surface getting balance. The difference between two models lies in their comprehension of emulsion droplet. Torque model provides more accurate description and couples more parameters than force balance model in case the diameter of large droplet during its detachment cannot be ignored. According to the framework of torques on a droplet as shown in Figure 1.10, the torques of adhesion and the torques of detachment can be grouped. It indicates that the rules of torques manipulate the droplet behaviors and can be examined by coupling operation parameters, membrane parameters, and physiochemistry properties of two phases. Therefore, we build a multivariable torque model to obtain the influences of different parameters on droplet detachment mechanism. Before multivariables torque model, two sets of relationships associating the dispersed phase parameters and the continuous phase parameters should be firstly constructed given in the following sections.

Figure 1.9 Schematic representation of contact line (top view) for a circular shape forming the droplet basis.

Figure 1.10 Torques and forces on droplet at membrane outlet. Source: Hao et al. [13]/with permission of American Chemical Society.

1.2.3.1 Associating the Dispersed‐Phase Parameters

During droplet growing up at membrane pore, the dispersed phase flow rate Qdr through the membrane pores may be assumed based on Darcy law and Hagen–Poiseuille equation as follows [11]:

(1.9)

where dp is membrane pore and here used 5.2 μm, ξ is the pore tortuosity and here approximatively used as 2.1, which was measured and calculated with hydraulic membrane resistance by Vladisavljevic [8], μd is the viscosity of dispersed phase, and L is the membrane thickness. Pef is the effective transmembrane pressure to control the dispersed phase and defined as the difference of two pressures,

(1.10)

where Ptrm is the transmembrane pressure applied in emulsification between each side of membrane, and Pγ is the capillary pressure.

The dynamic droplet volume Vd can be related to dispersed‐phase flow rate Qdr by following continuity equation of dispersed phase, as given below:

(1.11)

and the volume of droplet as a spherical cap can be calculated with the growing height h(t) of droplet at membrane pore as follows:

(1.12)

The dynamic height of droplet h (t) can thus be deducted by (1.11), (1.12), and (1.9),

(1.13)

Droplet diameter ddr (t) can also be described by height of droplet h (t),

(1.14)

So, the droplet growth ddr (t) can be deducted from Eqs. (1.13) and (1.14):

(1.15)

The initial conditions for Eqs. (1.14) and (1.15) are established according to Laplace equation with initial interfacial tension and critical pressure,

where h (0) is also determined by Eq. (1.14).

1.2.3.2 Associating the Continuous Phase Parameters

The shear force τw is the function of the continuous phase velocity uc[29],

1.16

where ρc is the density of continuous phase, uc is the flow velocity of continuous phase, and f is a dimensionless factor defined by the Reynolds number Re as Equ. 1.6.

1.2.3.3 Torque Balance Model Associating Operation Parameters

Among all the aforementioned forces on droplet, Fγ is the holding force, while Fp, Fγm, FBG, Fm, and Fτ are detaching forces. The inertia force Fm and the buoyancy force FBG, can be neglected after calculation considering that they are approximately from six to eight orders of magnitude smaller than other forces. So, all the torques on droplet can be grouped as follows:

the torque of adhesion,

(1.17)

and the torque of detachment,

(1.18)

If the adhesion torque (or interfacial tension) was very large at the balance point of two torques, Tadhesion = Tdetach, the droplet would be difficult to break off and a larger detachment torque (shearing stress) was needed and tend to be dragged by the SHE mechanism instead of the STB mechanism [31]. Therefore, we put forward that the torques at the balance point could act as a comparison criterion to estimate the transformation of the droplet detachment mechanism and further the emulsion uniformity, inspired by that droplet spontaneous formation (STB mechanism) is one of the most important mechanisms to form a uniform emulsion [13]. Since the torque model is constructed by coupling the operating parameters, the membrane parameters, and the physiochemistry properties of the two phases, the disturbances of these parameters on torques can be calculated to predict their influences on emulsion uniformity. Based on above mechanisms and parameters associated in torque models, we further explored the rules of controlling emulsion uniformity by experiment and theoretical approaches [13].

1.2.3.4 Evaluation of Controlling Factors on Droplets Uniformity by Torque Balance Model

Accordingly, the influence of operation conditions, the physical properties of two phases, and the membrane parameters on droplet formation and emulsion uniformity were systemically investigated by evaluating the variable force torques in droplet formation process. The experiment phenomena showed a good coincidence with model prediction. The conditions facilitating the production of uniform droplets were summarized as: (i) the high enough interfacial tension between the dispersed phase and the continuous phase, (ii) low cross‐flow velocity of the continuous phase, (iii) low transmembrane pressure, (iv) high viscosity of the dispersed phase, and (v) an emulsifier with great ability and rapid rate to decrease interfacial tension.

1.2.3.4.1 Influence of Continuous Phase Flow on Emulsion Uniformity

The flow rate of continuous phase is a fundamental process parameter to determine membrane emulsification efficiency because the wall shear stress by continuous phase is the major force to drive the droplets detaching from membrane pore. The effects of different continuous phase flow rates on emulsion uniformity were investigated by O/W emulsification experiments. Figure 1.11 shows that the distribution of droplet size (CV%) can keep narrow at a wide range of the continuous phase flow rate from 0.188 to 1.85 m s−1. However, with further increase of continuous phase flow from 1.85 to 3.95 m s−1, the droplet size distribution changed to broad quickly. Figure 1.11 also compared the relationship between droplet size distribution and the related predicted torques at balance. A general tendency was found that the emulsion uniformity (CV%) was spoiled at large detachment torque (at balance point) with continuous flow rate increases.

Figure 1.11 Influence of continuous phase flow velocity on droplet size distribution by experiment and detachment torques analysis. Source: Hao et al. [13]/with permission of American Chemical Society.

Figure 1.12