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4.3.4 Dynamic Stability 132
4.3.4.1 Brownian motion 132
4.3.4.2 Sedimentation and
sedimentation equilibrium 133
4.3.4.3 Interparticle interactions 134
4.3.5 Thermodynamic Stability 136
4.3.5.1 Electrical double layer theory
and zeta potential 137
4.3.5.2 Electrolyte 138
4.3.5.3 DLVO theory 140
4.3.5.4 Stability in aqueous system 142
4.3.5.5 Impact of polymer compounds
on stability 145
4.4 NPP of Inorganic Particles 146
4.4.1 Properties of Inorganic Nanoparticles 146
4.4.1.1 Electronic and optical
properties 146
7
8
4.4.1.4 Thermal properties 148
4.4.2 Biological Application of Inorganic
Nanoparticles 149
4.4.2.1 Au nanoparticles 149
2
4.4.2.3 Quantum dots 153
4.4.2.4 Carbon nanotubes 154
4
4.5 Summary and Perspective 155
5. Nano Physical Pharmaceutics of Nanogel Delivery
System 161
Xiaoling Pan, Jing Liu, Xiangling Gu, Na Fan, Wan Sun, and Wei Li
1
5.2 Preparation of Nanogels 162
x
Contents
4.3.3.2 Control of growth phases 130
5.2.2 Chemical Cross-Linking Reaction 163
5
tion 165
5.3.1 Cross-Linking of Nanogel 166
5.3.1.1 Gelation theory of nonlinear
polycondensation 166
5.3.1.2 Free radical addition
polymerization 167
5.3.2 Properties of Polyelectrolyte Nanogels 168
5.3.3 Structure and Stability of Nanogel 169
5.4 NPP of Nanogels in Drug Delivery 170
5.4.1 Physiochemical Properties of Nanogels 170
5.4.1.1 Expansion of nanogels 171
5.4.1.2 Swelling mechanism 172
swelling 174
of nanogels 175
5.4.2 In vivo Circulation of Nanogels 176
5.4.3 Drug Release Behavior of Nanogels 178
Drug-Loaded Nanogels 180
5.4.4.1 Drug-loading methods 181
2
5.4.4.3 Solvent 182
5.4.4.4 Particle size 183
5.4.4.5 Surface charge 183
5.4.5 Drug Release Behavior of
Stimulus-Responsive Nanogels 184
5.4.5.1 Temperature-responsive
nanogels 185
5.4.5.2 pH-responsive nanogels 186
5.4.5.3 Glucose-responsive nanogels 186
Contents
xi
2
5.4.5.4 Photoresponsive nanogels 187
5.4.6 Biological Applications of Nanogel
Delivery Systems 188
5.4.6.1 Delivery of small-molecule
therapeutic drugs 188
5.4.6.2 Delivery of oligonucleotides 189
5.4.6.3 Delivery of therapeutic
proteins 191
5.5 Summary and Perspective 191
6. Nano Physical Pharmaceutics of Microsphere
Delivery System 197
Zhiwen Qiu, Wanru Tao, Man Wang, Hanwen Sun, and Wei Li
7
9
9
6.2.2 Solvent Evaporation 200
6.2.3 Phase Separation 201
1
6.2.5 Spray Drying 202
3
3
tion 204
DLVO Theory 204
6
8
6.3.3.1 Properties of polymers 208
6.3.3.2 Surface charge of microspheres 210
1
6.4.1 Physicochemical Properties of
1
xii
Contents
5.4.5.5 Other stimulation-responsive
nanogels 188
9
Contents
xiii
6.4.1.1 Particle size and apparent
Preface
improvement, development of novel therapeutic modalities, and
reduction in medical expenditures. The challenge, however, is
that specially designed and carefully synthesized nanomedicines
function poorly in animal models despite great performance
in vitro. We believe a deeper understanding of the physicochemical properties of nanomedicine, that is, nano physical
pharmaceutics, is the key.
This book addresses the “bottleneck” of nano-based
formulations by focusing on clinical translation and applies
physical theories and models to determine the parameters for
controlling the physicochemical properties of nanomedicines,
including micelles, liposomes, and inorganic nanoparticles.
Qualitative and quantitative relationships are established to guide
nanomedicine design, characterization, and analysis. The book
also compiles cutting-edge research in nanomedicine from the
interdisciplinary team of the Department of Nanomedicine at
characteristic discipline called Nano Physical Pharmaceutics.
Edited by Wei Li, a prominent nanotechnology researcher, this
book will appeal to anyone involved in nanotechnology, medicine,
macromolecular science, biology, and chemistry, especially those
with an interest in drug delivery or cancer therapy. The book has
been accomplished with contributions from the team members,
Duan, Dr Junfang Li, and Dr. Hanwen Sun.
The guidance from Prof. Chi Wu, Prof. Huiming Hou,
Prof. Hao Wang and Prof. Jian Wang and the grant of the National
xvi
Preface
Natural Science Foundation of China, the Program of Shanghai
Academic Research Leader et al. are appreciated.
chemistry, polymer, physicochemistry, biology, and pharmaceutics.
The context and the logical illustration of the mechanism of the
kinetics and dynamics of polymer chains in solutions have been
cited from references. The theory and application of laser light
scattering have been cited from the editor’s PhD thesis. Both
citations are appreciated [1–3]. However, as some misspellings
or other mistakes in the text cannot be ruled out, the readers’
suggestions for any improvements are welcome.
Wei Li
Department of Nanomedicine
Naval Medical University
Shanghai, China
August 2024
References
1. T
eraok a I,
2002.
Press, 2019.
PhD thesis, The Chinese Uni
Fu XC, Hou WH,
ceutic
Polymer Solutions
A Concise Textbook of
Reexamination of Dynamic
Physical Chemistr
HM, Wang H, GJ, Technology of Pharma-
al Excipients, 2nd ed., China Medical Science Press, 2002.
versity of Hong K
Zhang
, John
Wiley & Sons, Inc, New York,
Thermodynamics
of Semidilut
y, Higher Education Press, 2022.
, Higher Education
e Polymer Solution,
ong, 2006.
Chapter 1
The Fundamentals and Powerful Tool for
Nano Physical Pharmaceutics (NPP)
Ziya Xia, Yening Xia, and Wei Li
Department of Nanomedicine,
Naval Medical University, Shanghai 200433, China
liwei_dds@163.com
1.1 Polymer Chains Behavior in Solutions
For a certain polymer, some solvents (good solvents) dissolve it
well, some solvents (bad solvents) cannot, and solvents whose
solubility is between the good and bad solvents will dissolve it to a
certain extent. With the variation of temperature or concentration
of the polymers, phase separation may take place, resulting in
aggregation of the polymers. In this section, we will introduce
the compatibility theory of polymers-solvent, as well as the
self-assembly mechanism of polymers.
1.1.1 Basic Interaction of Polymer Chain in Solution
[1–3]
1.1.1.1 Introduction to the c parameter
From the viewpoint of thermodynamics, if the polymers are soluble
in solvents, the dissolution process must reduce the free energy of
Nano Physical Pharmaceutics
Edited by Wei Li
Copyright © 2025 Jenny Stanford Publishing Pte. Ltd.
ISBN 978-981-4968-52-2 (Hardcover), 978-1-003-51393-3 (eBook)
www.jennystanford.com
2
The Fundamentals and Powerful Tool for Nano Physical Pharmaceutics
the system. The free energy of mixing of the system is as follows
[1]:
DGm = DHm – TDS
m
(1.1)
where DGm is the free energy of mixing of the system, DHm is
the enthalpy of mixing of the system, DSm is the entropy of mixing
of the system and T is the absolute temperature. The change of
enthalpy of the system comes from the interaction change upon
mixing. Note that only short-ranged interactions are considered
here, containing van der Walls interactions (also referred to as
dispersions), hydrogen bonding, and dipole-dipole interactions.
The change of entropy is because the order of the system changes.
Since dissolution is always a process of entropy increasing
(DSm > 0), the enthalpy of mixing determines the sign of the
free energy of the system, that is, either the enthalpy of the
system decreases (DHm < 0) due to dissolution, or the product of
temperature and entropy of mixing must be larger than the
enthalpy of mixing, then dissolution occurs. Compared with
the low-molecular-weight solutes, the degree of freedom of the
polymer monomer is lower, so the increase of entropy of
mixing is far less than that of the low-molecular-weight solutessolvent system and the compatibility of the polymers-solvent
system will be much lower. The solvents dissolving a certain
polymer are only that which surround the polymer chain.
Flory–Huggins parameter, i.e., c parameter, is commonly
used to describe the interaction change upon mixing of polymer–
solvent system. A lot of solubility theories are based on the
c parameter
using the lattice model which considers the interaction between
adjacent ones only is described below [2, 3]. The lattice model
only considers interactions resulting from the contacts of adjacent
molecules in the sites. As shown in Fig. 1.1, the interactions
for a polymer–polymer (P–P) contact (i.e., contact of adjacent
polymer monomers), a solvent–solvent (S–S) contact, and a
polymer–solvent (P–S) contact are represented by ePP, e
SS
and ePS,
respectively. Due to the rearrangement of contacts as polymers
are mixed with the solvent, the total interaction energy changes.
3
Polymer Chains Behavior in Solutions
For example, there are four P–P and four S–S contacts in respective
lattice sites of the polymers and solvent before mixing, while
after mixing, two P–P and two S–S contacts are replaced by four P–S
contacts. Thus, the bond energy changes from 4e
SS
+ 4e
PP
to 4e
PS
+
2e
SS
+ 2e
PP
and the variation is 4e
PS
– 2(e
SS
+ ePP). For one contact,
the variation is e
PS
– (e
SS
+ ePP)/2. Then, c
product of the lattice coordinate Z and the energy change reduced
by kBT:
1
Z e (+e e )
PS PP SS
2
(1.2)
c =
kT
B
A negative c indicates that polymer–solvent contact is more
likely to occur when mixing, meaning that a negative c can
promote the polymer to dissolve. In contrast, A positive one
the polymer–polymer and solvent–solvent contacts.
Figure 1.1 Scheme describes the basic interacons of polymers in soluon.
1.1.1.2 Relationship between c parameter and stability of
the solution [2, 3]
In order to describe the stability of polymer solutions, the
concept of replacement chemical potential (D m
rep
) is introduced.
Replacement chemical potential is the change of the free energy
due to the removal of solvent molecules and the replacement of