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44
The Fundamentals and Powerful Tool for Nano Physical Pharmaceutics
1.4.3.3 Characterization of self-assembly of polymer
aggregates in solutions
Figure 1.13 describes the self-assembly process during which the
polymers aggregate from small particles into large particles with
the increase in temperature, and the number of chains in the
be used to indicate the in-suit inter-particles/chains aggregations
process or self-assembly process in solutions [63].
Figure 1.13 Polymer self-assembly with temperature increasing. Reproduced
with permission from [63].
1.4.3.4 Characterization of the morphology of nanoparticles
in physiological media
Figure 1.14 shows the change in particle size and morphology of
nanoparticles characterized by light scattering in our previous
work. With the increase of the surface chain density, the stability
of particles increases, forming a single particle, which cannot be
adsorbed by serum proteins. The well-separated peaks of BSA
and delivery systems indicate the stability of the drug delivery
in serum solution with high concentration. This is a useful
evaluation method for evaluating the in vivo serum stability of
nanoformulations.
The Powerful Tool for Study of Nano Physical Pharmaceutics
45
Figure 1.14 Characterizaon of the morphology of nanoparcles in
physiological media by light scaering. Reproduced with permission from [64].
1.4.3.5 Well-defined nanogel in-suit preparation by radical
co-polymerization and indicated by LLS
Figure 1.15 shows the nanogel with core–shell structure, narrow
by light scattering in our group. The core and shell of nanogel in
the TEM image is quantitatively analyzed by red circle (core) and
blue circle (shell) with marked radius R, R
core
, R
shell
, the density of
core and shell (r
core
, r
shell
) on left panel. Then in the SLLS testing,
line as introducing the microstructural parameters into the
function of p(q), which indicates that the experimental data is
well observed with the theoretic curve. On the other hand, the
R
core
and R
shell
can be designed by tuning the feeding ratio of PEI
and PNIPAM monomers (A = W
PEI/WNIPAM
) by Equation 1.80 in
46
The Fundamentals and Powerful Tool for Nano Physical Pharmaceutics
the reaction [65]. Thus, according to Equation 1.80, the core–shell
structure can be easily tailored in the experiment.
R
g
(Ax
2
−+
(
1 Ax
5
.
3
)
+1
)
=
05
(1.80)
R
h
51( + A)(
1 − x
2
)
Figure 1.15 Nanogel with core–shell structure tailoring by LLS in our group.
Figure 1.16 Correlaons between the NPP and the in vitro/vivo performance.
Where: fZ: Surface potenal; r
surface chain
: Surface chain density; r
charge
:
Surface charge density; A2: Second virial eciency; CMC: Crical micellizaon
concentraon; D: Diameter; EPR: Enhanced permeability and retenon; HLB:
Hydrophilic lipophilic balance; N
agg
: Aggregaon number; N
Chain
: Chain number
in parcle; t
1/2
: Half me of circulaon; T: Temperature; V
core
: Core volume.
References
47
1.4.3.6 NPP of dierent delivery systems obtained by SLLS
delivery systems and the in vitro/vivo performance, which was
conducted and summarized by our group. These key parameters,
which are the basis of NPP discussed in this book, are discussed
in detail in the following chapters.
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Chapter 2
Nano Physical Pharmaceutics of
Micelle-Based Systems
Yening Xia, Ruochen Huang, Fei Duan, and Wei Li
Department of Nanomedicine,
Naval Medical University Shanghai 200433, China
liwei_dds@163.com
2.1 Classification of Micelle
Micelle refers to the ordered aggregate obtained by self-assembly
when the concentration of surfactant in the solution exceeds critical
micelle concentration (CMC). The compounds that form micelles
are generally amphiphilic molecules, which contain both hydrophilic
and hydrophobic chemical structures [1–2]. A single surfactant
molecule is surrounded by water molecules after being dissolved
in water. The hydrophilic group in the molecule is attracted by
water and the hydrophobic group is repelled by water, so it is
hydrophobic group to the air. When the concentration of the
surfactant increases to the point where the surface of the solution
reaches saturation and cannot continue to be adsorbed, it transfers
to the inside of the solution. After reaching a certain concentration,
the hydrophobic groups in the molecule attract each other and
Nano Physical Pharmaceucs
Edited by Wei Li
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ISBN 978-981-4968-52-2 (Hardcover), 978-1-003-51393-3 (eBook)
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52
Nano Physical Pharmaceutics of Micelle-Based Systems
associate into groups, while the hydrophilic groups extend into the
water and combine with the water molecules to form aggregates
with hydrophobic kernel and hydrophilic shell, namely micelles.
Micelles and monomers in the solution are in kinetic equilibrium,
constantly breaking and recombining. A micelle is generally formed
by dozens or hundreds (50~200) of surfactant molecules. The
number of surfactant molecules in micelles is called the aggregation
number (m), and the aggregation number is multiplied by the
relative molecular mass of the surfactant to obtain the micelle
amount, that is, the relative micelle mass [1, 3].
surfactants according to the dissociation properties of their polar
groups. Table 2.1 lists the chemical structures of several common
surfactant hydrophilic groups [4]. The ionic surfactants usually
contain functional groups, such as thiol, ester, sulfate, sulfonate,
phosphate and amide. In non-ionic surfactants, the hydrophilic group
does not dissociate in aqueous solution, and these are commonly
polyethylene glycol (PEG, (–CH2CH2O–)n)-based structures. Micelles
Table 2.1 Chemical structures of common surfactant hydrophilic groups [4]
Name Type of Surfactant Structure
Carboxylate Anionic
R—(COO
–
)nM
n+
Sulfonate Anionic R—SO
3
–
M
+
Thiocarboxylate Anionic -O3S—RCOO—M
2+
Ammonium salt Cationic
Cationic
Phosphate Cationic
R
R N R
R
R S
R
2
R
P R
R
R
1
X
2
3
R
X
1
1
X
2
3
Classification of Micelle
53
Table 2.1 (Continued)
Name
Pyridine
Type of Surfactant
Cationic
Structure
Polyoxyethylene
fatty alcohol ether
Polyoxyethylene
ester
Polyoxyethylene
alkyl thioether
Triglycine
Non-ionic
Non-ionic
Non-ionic
Amphoteric
R-(OCH
2CH2)n
-OH
R-COO-(CH
2CH2)n
-OH
R-COO-(CH
2CH2O)n
-OH
2.1.1 Ionic Surfactant Micelle
The hydrophobic portions of surfactants attract each other
and associate with each other to form the inner core, while the
hydrophilic groups are arranged on the surface of the core, and
discovered that micelles were spherical when the concentration
of surfactant was slightly greater than CMC without the presence
that micelles are spherical and the degree of association remains
unchanged when the concentration is greater than CMC within a
certain range. The shape also may vary from spherical depending
upon the chain length and the area occupied per polar group on
the surface. Debye et al. found that micelles are rod-shaped in
concentrated solution, which has higher thermodynamic stability.
When the concentration increases further, micelles aggregate as
bundles or superimpose as layers [6].
2.1.2 Non-Ionic Surfactant Micelle
For example, the micelle is reticulated when the degree of
R N X
CH2COOH
N
R
CH
CH
2
CHOO
2
COOH