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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5580_Библиотеки_им_академика_М_И_Перельмана
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350 H. Yamamoto
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Fig. 19.14 Relationship between Rf value and molecular volume
Fig. 19.15 HSP distance corrected by molecular volume
19.4.2 High-Performance Liquid Chromatography (HPLC)
HPLC is used not only for analysis but also for fractionation of the main components.
Silica gel modified with octadecane on its surface is packed in a column. When
multiple components dissolved in a carrier are poured through it, the compounds
are separated according to the degree of interaction with octadecane as shown in
19.16.
Fig.
The time from injection until it reaches the detector is called retention time. Data
from a simultaneous HPLC analysis of psychotropic drugs (Table
analyzed.
Molecular structures are diverse and retention times are generally difficult to
predict. The shorter the solute’s HSP distance from the octadecane HSP, [δD, δP,
19.4)[7
]were
19 Formulation Using Hansen Solubility Parameters 351
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Fig. 19.16 Separation mechanism in high-performance liquid chromatography
Table 19.4 Retention time for psychotropic drugs
Chemical CAS RT
Ethosuximide 77-67-8 1.329
Primidone 125-33-7 1.458
Sultiame 61-56-3 1.596
5-(4-Hydroxyphenyl)-5-phenylhydantoin 2784-27-2 2.295
Phenobarbital 57-30-7 2.436
Carbamazepine 85756-57-6 3.155
Phenytoin 57-41-0 3.216
Nitrazepam X 3.403
Clonazepam X 3.768
Valproic acid X 4.732
Diazepam 53320-84-6 5.104
δH ] = [16.4, 0.0, 0.0], the greater the interaction and the greater the retention time.
The larger the molecular volume, the longer the retention time.
This may be because large molecules are difficult to re-dissolve in the polar solvent
of the mobile phase once they dissolve in octadecane of the stationary phase.
As the result, HSP distance/MVol has a correlation with Retention Time as shown
in Fig. 19.17.
352 H. Yamamoto
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Fig. 19.17 Correlation between retention time and HSP distance/molecular volume
19.5 Interaction of Pharmaceuticals and Macromolecules
Purified pharmaceuticals are exposed to stomach acid as soon as they enter the body. If
they do not want to be decomposed by hydrochloric acid, they are adjusted in complex
with polymers or inorganic substances. In most cases, cellulose- or starch-based
polymers are used. When attempting to design more highly functional complexes,
the interaction between the pharmaceuticals and polymers is evaluated using HSP.
19.5.1 Preparation With Cyclodextrin
Cyclodextrins have a bottomless bucket-like structure with 6–8 D-glucose rings as
shown in Fig.
Pharmaceuticals can be encapsulated in this cavity. It is used to increase the
solubility of pharmaceuticals. The inclusion constants of this α-cyclodextrin and
pharmaceuticals were collected from the literature [
stability constants (K:M-1) are shown in Fig.
It can be seen that if the molecule is flat or has polar groups, the stabilization
constant becomes smaller. Since the HSP of the cavity of cyclodextrin cannot be
determined, a multiple regression equation was created using the HSP values of the
drug product and the molecular volume. The results of the regression calculation are
shown in Fig.
log K
Equation (19.12) shows that the stabilization constant decreases as the dispersion
term (δD) and the hydrogen bonding term (δH) of Hansen’s solubility parameter
increase. The s tabilization constant increases as the polar term (δP) and molecular
19.18.
8
]. The molecular structure and
19.19.
19.20.
=−0.2001∗δD + 0.090∗δP − 0.047∗δH + 0.008∗MVol + 3.318
calc
(19.12)
19 Formulation Using Hansen Solubility Parameters 353
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Fig. 19.18 Structure of
cyclodextrin
Fig. 19.19 Molecular structure and stabilization constant
354 H. Yamamoto
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Fig. 19.20 Stabilization constant and calculated value of Eq. (19.12)
Fig. 19.21 Smallest cube
surrounding a molecule
Norm3rd
Norm1st
n
2
m
r
o
N
volume (MVol) increase. For more accurate estimation equation, the degree of fittings
of cyclodextrin to the cavity and the HSP of the cavity may be necessary.
Many researchers would assume that to obtain a high stabilization constant, the
molecule should be elongated so that the entire molecule fits into the cavity of
the cyclodextrin. I calculated the smallest rectangular Fig.
19.21 that the molecule
considered here will fit into. The longest edge is Norm1st, the next longest is
Norm2nd, and the shortest is Norm3rd.
The highest correlation with the stabilization constant was found for Norm2nd,
and as shown in Fig.
19.22, the stabilization constant increased as Norm2nd became
longer.
The exceptions were diazepam and indomethacin. Inclusion of cyclodextrins can
be either “sitting” with part of the molecule in the cavity, or inclusion of only the longchain alkyl groups, leaving the hydrophilic part outside the cavity. In some systems,
multiple cyclodextrins and a single compound can form inclusion complexes. These
differences are expected to cause exceptions.
d
19 Formulation Using Hansen Solubility Parameters 355
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Fig. 19.22 Stabilization constant and Norm2nd
19.5.2 Design of Microspheres for Drug Release Using HSP
A typical microcapsule for DDS is prepared by the following scheme (Fig.
19.23).
It is very difficult to design a balanced interaction between polymer, API, and
].
solvent. Such microspheres are designed using Hansen solubility parameters [
9
Active Pharmaceutical Ingredient (API) is 3-{2-{2-[4-(6-Fluor-1,2-benzisoxazol3-yl)piperidino]ethyl}-2-methyl-6,7,8,9-tetrahydro-4H- pyrido[1,2-a]pyrimidin-4on, CAS: 130049-83-1 is used. If the HSP of the polymer, API, and solvent match,
a stable solution can be made. This is emulsified and the solvent is removed. The
drug will then precipitate into the polymer. The drug is gradually released from the
microparticles, and the speed of release is strongly dependent on the solvent used to
make the microparticles.
Poly(lactide-co-glycolide) 75:25 (PLGA) was used here as the polymer. From
the data of the degree of swelling of PLGA in solvent, good and poor solvents are
Fig. 19.23 Scheme for making microcapsules for DDS
356 H. Yamamoto
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Fig. 19.24 Solvent, API and
PLGA plotted in Hansen
space
defined. The Hansen solubility sphere, with the good solvent inside the sphere and
the poor solvent outside the sphere, was determined using HSPiP software. The HSP
of the center of the Hansen solubility sphere, i.e., PLGA, was obtained as [δD, δP,
δH ] = [17.4, 8.3, 9.9]. The HSP of API was calculated from the actual solubility
data using HSPiP software and obtained as [δD, δP, δH ] = [19.5, 7.1,9.7]. This is
shown in Hansen space as Fig.
19.24. API is soluble in PLGA because it falls inside
the Hansen solubility sphere.
When the HSP distance between the polymer and API is long, the solvent is
homogeneous during dissolution, but phase separation occurs when the solvent is
removed after emulsification.
Methylene Chloride is located close to PLGA and API, indicating that it is a
suitable solvent for dissolving both. In this paper, methylene chloride and benzyl
alcohol or a mixture of methylene chloride and n-butanol are used. benzyl alcohol is
a good solvent for API. n-Butanol is a poor solvent because of its long HSP distance.
Methylene chloride is a good solvent for API, but it is highly volatile. Therefore, after
the volatilization of methylene chloride, API crystallizes slowly in Benzyl alcohol.
n-Butanol is a poor solvent, so API precipitates as amorphous. If the HSP distance
between the HSP of the solvent mixture and PLGA is short, PLGA is well soluble.
Therefore, Fig.
19.25 shows that the drug released after 25d from microspheres
prepared from the solvent mixture tends to be smaller, probably due to the increased
denseness and homogeneity of the PLGA film.
In this case, whether the API was crystalline or amorphous had no effect on API
release. However, if crystallinity can be designed by controlling HSP, the range of
applications is very wide.
19 Formulation Using Hansen Solubility Parameters 357
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Fig. 19.25 Relationship between HSP distance from PLGA and API release
References
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