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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5858_Библиотеки_им_академика_М_И_Перельмана
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340 H. Yamamoto
https://t.me/med1917
Fig. 19.5 Hansen space representation of HSP of raw materials and products (a) and solvent search
(b)
Also, if the structure and HSP of the raw materials and by-products are known, it
is possible to design a solvent that dissolves only what is desired to be removed.
The raw material of paracetamol is 4-Aminophenol, which has calculated HSP
values of [20.2, 8.3, 17.2]. Its position in Hansen space is shown in Fig.
19.5a. Then,
the position of the red star on the line segment created by the tips of the two vectors
19.5b has the longest HSP distance from paracetamol, and 4-Aminophnol is
in Fig.
the HSP that dissolves. The solvent at the opposite position will dissolve the product
and not dissolve the raw material. Which one is chosen depends on the yield.
19.2.2 How to Select Safe Solvents Using HSP
Pharmaceuticals that enter the body directly are subject to strict regulations on
solvents used in the formulation process. Residual solvent guidelines for pharmaceuticals have been recommended by International Council for Harmonisation of
Technical Requirements for Pharmaceuticals for Human Use (ICH).
Class 1: Solvents to be avoided in the manufacture of pharmaceuticals:
Benzene, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethene, 1,1,1trichloroethane.
Class 2: Solvents whose residues in pharmaceutical products should be
regulated: Acetonitrile, chlorobenzene, chloroform, cumene, cyclohexane, 1,2dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide,
N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol,
formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methyl
isobutyl ketone, methyl cyclohexane, N-methyl pyrrolidone, nitromethane, pyridine, sulfolane, tetrahydrofuran, tetralin, toluene, 1,1,2-trichloroethene, xylene
(ortho and Toluene, 1,1,2-trichloroethene, xylene (ortho, para, meta).
19 Formulation Using Hansen Solubility Parameters 341
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Class 3: Low toxicity solvents:
Acetic acid, acetone, anisole, 1-butanol, 2-butanol, n-butyl acetate, t-butyl methyl
ether, dimethyl sulfoxide, ethanol, ethyl acetate, diethyl ether, ethyl formate, formic
acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1Butanol, methyl ethyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol,
2-propanol, propyl acetate, triethylamine.
However, if it is to be used as a solvent for a pharmaceutical product, it must
dissolve the pharmaceutical product. Therefore, pharmaceuticals using Class 2
solvents must either have their residual solvents strictly controlled or be switched to
Class 3 solvents (mixed solvents).
In the case of paracetamol, the solvent that dissolves best is dimethyl sulfoxide.
Since this is a Class 3 solvent, there is no need to explore other solvents, but I will
explain how to use Hansen’s solubility parameters to design a mixture of solvents.
Hansen’s solubility parameter for mixed solvents can be calculated by the volume
fraction of the solvent as shown in Eq. (
dissolved when a mixed vector of poor solvent solvents as shown in Fig.
19.5). There are many examples of solutes
19.6 is
placed inside Hansen’s solubility sphere.
δD
[
,δPm,δH
m
a ∗ δD
(
=
]
m
+ b ∗ δD
1
a + b
(
)
(
)
2
a ∗ δH
a ∗ δP
(
,
+ b ∗ δH
1
a + b
(
1
a + b
(
)
+ b ∗ δP
)
)
2
)
2
,
(19.5)
To find the solvent that best dissolves Paracetamol (HSP = [17.7, 14.0, 17.5])
from only Class 3 solvents, use HSPiP software (Fig. 19.7). To optimize the Class
3 solvent composition, a solvent set named Q3C-ICH-2017.sofx has been prepared.
The design of the solvent mixture for Paracetamol is as follows.
Originally, ethanol and DMSO, which are good solvents, are Class 3 solvents, and
a mixture of Ethanol and DMSO at 61:39 by volume was calculated to have the HSP
distance of 3.5. Specifying not to use DMSO, a mixture of ethanol and Acetone at
81:19 was calculated to have the HSP distance of 6.3. Thus, it is effective for solvent
design to start from mixtures suggested by solubility parameters, rather than trying
mixtures without any specific solvents at all.
Fig. 19.6 Hansen solubility
parameters for mixed
solvents
342 H. Yamamoto
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Fig. 19.7 Solvent optimization function of HSPiP
19.3 Selection of Crystallization Solvent Using HSP
The compound does not dissolve in the solvent above its saturation solubility. If the
saturation solubility is increased by raising the temperature, crystals will precipitate
upon cooling. If the raw materials and by-products are below saturated solubility
at that time, the purity of the crystals will be high. Poor solvent crystallization,
in which the solubility is lowered by adding a poor solvent without changing the
temperature, has also been put to practical use. As a special crystallization method,
the development of co-crystal melting agents to control the solubility of crystals has
been conducted using HSP.
19.3.1 Temperature Effects When Performing Crystallization
As the temperature of the solvent is increased, the HSP becomes smaller. This is
clear from Eq. (
of evaporation becomes. The temperature dependence of HSP is expressed by Eqs.
19.6–19.8), where α is the coefficient of thermal expansion.
(
From the HSP concept, the temperature effect is considered as follows. The higher
the temperature, the smaller the HSP of the solvent. Since the HSP of a solute changes
little with temperature (the thermal expansion coefficient of a solid is negligible),
dissolution occurs when the smaller HSP matches the smaller HSP of the solute.
19.3), since the higher the temperature, the smaller the latent heat
d
δD =−1.25 · α · δD (19.6)
dT
d
δP =−α · δP (19.7)
dT
d
δH =−1.22 · 10
dT
−3
α
δH (19.8)
+
2
19 Formulation Using Hansen Solubility Parameters 343
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For example, this is the case when fluorinated polymers dissolve in cycloalkanes
at high temperatures. In many cases, however, the effect of temperature becomes a
kinetic problem. HSP can handle the thermodynamic problem, but not the kinetic one.
Thermodynamics can indicate the direction of dissolution, but the rate of dissolution
is a kinetic problem. The effect of temperature on dissolution varies greatly in relation
to the melting point (glass transition temperature) of the solute. If the test temperature
of dissolution is above the melting point, the dissolution rate will be very fast.
Therefore, the temperature effect on solubility is treated as a QSAR study. The
solubility data for ibuprofen were obtained from the literature [
4].
Solubility in solvents increases rapidly with increasing temperature as shown in
19.8. However, the HSP value does not decrease by 1%. The QSAR equation for
Fig.
solubility prediction is constructed using HSPiP software. The built-in QSAR equation construction function automatically selects not only HSP values but also various
thermodynamic properties (Fig.
19.9). The proposed QSAR equation is Eq. (19.9).
log(Solubility) = 5.05 − 0.0686 ∗ δD + 0.00423 ∗ δP + 0.00826 ∗ δH
− 1.31 ∗ Ovality + 0.0207 ∗ UserT (19.9)
− 0.00571 ∗ δH
Don
Acc
Ovality, which represents the sphericity of the molecule as well as the HSP value,
was chosen for Eq. (
19.9). Ovality is 1 for a perfect sphere and increases as the
molecule deviates from a spherical shape. The coefficient is negative, suggesting
that the solubility of ibuprofen is smaller in non-spherical solvents.
Fig. 19.8 Temperature dependence of solubility of ibuprofen in various solvents
344 H. Yamamoto
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Fig. 19.9 Solubility calculation of ibuprofen using Eq. (19.9)
19.3.2 Crystallization in Poor Solvents
When a saturated solution of a compound is added to a poor solvent, the compound
precipitates as crystals. This operation i s called poor solvent crystallization. When
performing this operation, it is important to determine whether the added poor solvent
will dissolve in the original solvent. In general, polar and non-polar solvents do not
mix. Therefore, adding hexane to a DMSO solution of paracetamol will not cause
poor solvent crystallization. However, ethanol, for example, will mix with both nonpolar and polar solvents. Particularly small compounds with polar groups biased to
one side of the molecule will mix with solvents of both polarities, such as surfactants.
Although there are such exceptions, most solvents should not be mixed if they are
far apart in HSP distance. Particularly difficult to determine whether or not to mix
are solvents that form networks in solution. The solubility parameter can be obtained
from the latent heat of evaporation of the solvent at 25 °C and the molecular volume
using Eq. (
is highly correlated with the boiling point as shown Fig.
called Trouton’s general rule.
As functional groups are introduced into the molecule or the molecule becomes
larger, the boiling point increases, but the latent heat of evaporation also increases
proportionally. Such solvents are called regular solutions. In contrast, alcohols and
carboxylic acids, which create a network of hydrogen bonds, require more energy
to break the network. Therefore, solubility parameters can be divided into a regular
solution and a network. The energy of evaporation for the regular solution portion
is E = 85 * boiling point, based on the relationship between the boiling point and
the latent heat of evaporation. Therefore, the solubility parameter δ
19.3). It is known that the latent heat of evaporation at the boiling point
19.10. This correlation is
of the normal
Reg
19 Formulation Using Hansen Solubility Parameters 345
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Fig. 19.10 Relationship between the boiling points of various solvents and the latent heat of
evaporation at the boiling point
solution can be expressed by Eq. (19.10).
=
85 ∗ BP
MVol
δ
Reg
(19.10)
where BP is the normal boiling point and MVol is the molecular volume at 25 °C.
Since the total solubility parameter, δ
, is known, the solubility parameter δ
T
the network can be calculated using Eq. (
2
δ
= δ
Net
Solvents with large δ
will not mix with solvents other than those that can
Net
19.11).
2
− δ
T
2
Reg
for
Net
(19.11)
reconstruct the network. In particular, solvents that have multiple functional groups
and create a three-dimensional network have a large δ
and can only be mixed with
Net
a limited number of solvents.
19.3.3 Co-Crystal Preparation Using HSP
A co-crystal is a homogeneous solid phase containing two or more neutral molecular
components in a stoichiometrically defined crystal lattice, solid at room temperature, and bound together mainly by weak interactions such as hydrogen bonds. The
greatest significance of considering co-crystallization is that the properties of the
second component incorporated in the crystal structure are reflected in the solid
(crystal) properties, thus improving the solubility and bioavailability of the API
without modifying the chemical structure of the active ingredient. The success or
346 H. Yamamoto
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failure of the co-former and co-crystal preparation of indomethacin was obtained
].
from a paper [
5
HSP, molecular volume, and Ovality of co-former in Table 19.2 were calculated
using Y-MB of HSPiP. HSP of indomethacin was [δD, δP, δH] = [19.7, 6.5, 7.7].
In order to become a co-crystal, the HSP distance between indomethacin and the
co-former must be less than 10. However, there are many co-formers that do not
become co-crystals even if the HSP distance is less than 10. The size of the molecule
and the shape factor Ovality of the molecule are also considered to be influential.
Although a different system from HSP, donor/acceptor interactions should be
explained. Indomethacin is a compound with a carboxyl group and 4,4’-BiPyridine
is a compound with a pyridine ring. This pair is not only close in HSP distance but
also greatly stabilized by rearrangement as shown in Fig.
19.11 of Electron Donor/
Acceptor.
Table 19.2 HSP of Indomethacin and co-crystal formation
Co-former δD δP δH Cocrystal HSP Distance MVol Ovality
4,4’-Bipyridine 19.79 7.26 5.43 Yes 2.4 137.3 1.43
4-Aminobenzamide 20.41 13.43 15.21 No 10.3 112.1 1.509
p-Aminobenzoic
Acid
4-Hydroxybenzoic
Acid
Benzoic Acid 20 6.9 10.8 No 3.2 112.4 1.455
Cinnamic Acid 18.77 5.4 10.46 Yes 3.5 132.2 1.466
Citric Acid 18.32 11.07 27.35 No 20.4 122.7 1.564
Cyclohexylsulfamic
Acid
Fumaric Acid 18.22 10.34 20.58 No 13.8 85.8 1.512
Glutaric Acid 17.16 9.44 18.64 No 12.4 108 1.534
Maleic Acid 18.22 10.34 20.58 No 13.8 85.8 1.512
Malic Acid 18.28 12.01 26.71 No 20.0 90 1.548
Malonic Acid 17.77 11.31 22.12 No 15.7 74.9 1.508
Neotame 17.62 7.01 9.74 No 4.6 338.8 1.751
Niacinamide 19.78 14.95 12.47 Ye s 9.7 100.4 1.415
Oxalic Acid 17 17 26 No 21.8 61.5 1.521
Saccharin 21.1 12.5 9.8 Yes 7.0 206.8 1.558
Succinic Acid 17.53 10.2 20.46 No 14.0 91.5 1.529
Urea 20.9 18.7 26.4 No 22.5 48.8 1.409
Vanillic acid 19.78 8.93 15.04 No 7.7 125.4 1.567
20.45 8.74 14.32 No 7.2 106.7 1.566
20.04 8.43 15.2 No 7.8 104.1 1.56
18.19 12.2 14.67 No 9.5 140.3 1.495
19 Formulation Using Hansen Solubility Parameters 347
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Fig. 19.11 Donor/acceptor rearrangement stabilization
Many co-formers that have short HSP distances but do not make co-crystals
have this stabilization energy small or have a positive sign and are destabilized by
rearrangements.
Those that do not co-crystallize become eutectic mixtures. A eutectic mixture
is a mixture of two or more crystals that precipitate simultaneously from a liquid
containing two or more components, also called eutectoid or eutectic mixture. The
active substance and the co-former form separate crystals but have a single melting
point. In many cases, the melting point is smaller than the melting point of the coformer alone. HSP is also used in the design of eutectic mixtures, since the melting
point drop is more pronounced at HSP distances around 7–15. In the future, HSP
distances and stabilization energies of rearrangements will be analyzed using chemoinformatics techniques, allowing co-formers to be screened efficiently.
19.4 Column Separation Design Using HSP
Column separation is also often used in the purification of pharmaceuticals. This
separation involves adsorption on a stationary phase, silica gel, and dissolution in a
mobile phase. Thin layer chromatography is often used for analysis prior to column
separation. The crude solution can be analyzed as it is after the reaction is complete.
Dividing the distance transferred b of the substance by the distance transferred a
of the solvent yields the Rf value. This Rf value is important information because
it corresponds to the time required for the target substance to be removed from the
column separation. High-performance liquid chromatography is also used for more
accurate analysis. In both cases, different components move at different speeds due
to differences in the interaction between the sample, stationary phase, and mobile
phase. Therefore, the differences in this interaction can be analyzed by HSP.
348 H. Yamamoto
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19.4.1 Rf Value of Thin Layer Chromatography
Table 19.3 shows the Rf values of the compounds when expanded with benzene [6
The Rf value is determined by the adsorption on silica gel and the solubility in
the developing solvent benzene. Therefore, I examined the HSP of common silica
gel, [δD, δP, δH ] = [14.9, 3.5, 4.6], and the HSP of benzene, [δD, δP, δH ] = [18.4,
1.5 2.0], and the HSP distances from these values.
As showninFig. 19.12, there was no correlation between the Rf value and the HSP
distance to silica gel. Compounds with inherently short HSP distances are expected
to interact strongly with silica gel. In that case, the Rf value should be smaller. It can
be seen that there is no such interaction.
Solvents with a short HSP distance from the developing solvent benzene should
tend to have a larger Rf value because they dissolve well in benzene. As shown in
19.13, the results are divided into two or three groups, but there is a clear tendency
Fig.
for the Rf value to increase as the HSP distance becomes shorter. It is a matter of
judgment for each researcher as to what additional items to add to understand this
phenomenon. Some researchers have automatically generated an equation to predict
the Rf value from various identifiers. The Rf value will be larger if the sample is easily
soluble in benzene, the solvent used for the development. Adsorption to silica gel was
considered as a mechanism to prevent this migration, but the HSP distance could not
Table 19.3 Rf and HSP values and molecular volumes of compounds
Name CAS Rf δD δP δH MVol
Nitroso benzene 586-96-9 0.45 18.73 7.41 5.84 96.8
p-Nitrotoluene 99-99-0 0.55 19.1 8.54 5.06 121.7
Benzyl alcohol 100-51-6 0.05 18.98 6 12.5 103.6
Benzophenone 119-61-9 0.35 19.42 5.43 3.77 164.3
Acetylacetone 123-54-6 0.1 16.99 10.97 6.79 102.1
Aniline 62-53-3 0.14 19.37 5.53 10.32 94.1
N-Methylaniline 100-61-8 0.25 19.04 5.24 7.9 109.8
Diphenylamine 122-39-4 0.6 19.71 4.1 6.34 156.3
Triphenylamine 603-34-9 0.75 19.53 1.85 4.2 221.7
Dibenzopyrrole Carbazole 86-74-8 0.5 20.66 6.15 5.48 138.3
2,4-Dimethylaniline 95-68-1 0.07 18.88 5.02 8.56 125.8
2,4-Dichloroaniline 554-00-7 0.4 20.19 6.95 9.11 118.6
Pyridine 110-86-1 0.04 18.89 7.53 6.85 80.3
Benzyl formate 104-57-4 0.63 18.14 5.62 6.73 125.8
Isobutyl acetate 110-19-0 0.5 15.58 4.47 5.59 132.9
Pentyl acetate 628-63-7 0.54 15.98 4.33 5.84 148.1
3-Methylbutyl butanoate 106-27-4 0.62 15.66 3.32 4.25 183.3
Hexyl butanoate 2639-63-6 0.68 15.96 3.36 4.43 199.2
].
19 Formulation Using Hansen Solubility Parameters 349
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Fig. 19.12 Rf value and HSP distance between compound and silica gel
explain it. I will consider the reason why the Rf values below and above 0.35 show
different behaviors. For example, I thought that large molecules might be difficult
to move even if they are dissolved. However, contrary to my expectation, Fig.
19.14
shows that the molecules with large Rf values have large molecular volume.
This result indicates that the effect of silica gel is not physical adsorption. It is
reasonable to assume that smaller molecules penetrate deeper into the gel and migrate
slower. This is the same mechanism as in gel permeation chromatography (GPC). If
I then change the vertical axis to the HSP distance divided by the molecular volume,
I obtain Fig.
19.15.
Large molecules that dissolve easily in the solvent benzene have large Rf
values. Benzophenone and 2,4-dimethylaniline are outliers. There may be a specific
interaction with silica gel.
Fig. 19.13 Rf value and HSP distance between compound and benzene
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