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Control of Polymorphism in Crystallization of Amino Acid.

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Dev. Chem. Eng. Mineral Process. 11(S/4), pp. 579-602,2003.
Control of Polymorphism in
Crystallization of Amino Acid
Mitsuta ka Kitamu ra*
Department of Chemical Engineering, Hiroshima University
1-4-1, Kagamiyama, Higashi-Hiroshima City, 739-852 7, Japan
The crystallization
mechanism
and
the
controlling factors
in
the
crystallization of amino acid polymorphs were investigated. It was
demonstrated that the effect of supersaturation (Ostwald's step rule) was not
observed for systems of either L-Glutamic acid (a, B) or L-Histidine (A, B).
The intensive effect of temperature was shown in the crystallization of
L-Glutamic acid (L-Glu) polymorphs, however, no temperature effect was
observed in the case of L-Histidine (L-Hisopolymorphs.
It was suggested
that such a difference could be related to the difference of the molecular
conformation between the polymorphs, and the contribution of the conformers
in the solutions to the nucleation process of L-Glu polymorphs.
of both L-Glu polymorphs (a and
nuclei-above-nuclei
mechanism.
B)
The growth
appeared to be due to the
With these results,
temperature
and
supersaturation appeared to be the basic important controlling factors (the
primary factors) of polymorphism.
Solvents and additives (the secondary factors) also have an influence on
polymorphism. The influence of ethanol compositions on the crystallization of
L-His polymorphs (A and B) was observed, and demonstrated that the solvent
* Email: mkitamu@hiroshima-u.ac.jp
5 79
M.Kitamura
effect is very kinetic, i.e. the nucleation and growth rate of the A form are
suppressed with an increase in the ethanol composition. The effects of
L-Phenylalanine as an additive on the crystallization and transformation rates
were shown in batch crystallization. The effect of L-phenylalanine on the
growth rate and morphologV of L-Glu polymorphs was also examined using
the single crystal method in a flow system. The relationship between the
additive concentration and the growth rate of each polymorph was expressed
by the proposed equation. The importance of the kinetics of the crystallization
for control of the polymorphic crystallization was demonstrated.
The
supersaturation needed for control of the selective crystallization of the
polymorph was also calculated. From these results the controlling factors for
the crystallization of polymorphs have been classified in order to clarifL their
complex interrelationship.
Introduction
The control of crystallization of polymorphs is eagerly demanded in industry
because the functionality and properties (e.g. bioavailability, morphology and
purity) of many kinds of materials depend on the molecular arrangement in
crystals. However, the precipitation behavior of polymorphous crystals is
usually complex and the crystallization mechanism is unclear. The
crystallization process of polymorphs is composed of the competitive
nucleation and crystal growth of the polymorphs, and the transformation from
metastable forms to stable forms. To control the polymorphism, the
dependence of the elemental steps in the crystallization upon the operational
factors should be determined [ 1, 21. Temperature and supersaturation are
fundamental conditions in normal crystallization, and these factors also have
an influence on the polymorphic crystallization [3]. The addition of
polymorphous seed crystals sometimes affects the crystallization behavior
[4-51, furthermore the crystallization of the polymorphs is frequently
influenced by additives [S-71. For example, it is known that the other amino
acids present as an impurity (additive) in solutions frequently have an
influence on the crystallization of the amino acid as a tailor-made additive.
580
Control of Polymorphism in C?ystallization of Amino Acid
The effect of amino acids as additives appears in the crystallization of amino
acid polymorphs [7]. The solvent is also a very important factor in industrial
crystallization [8-101 and is effective on the polymorphism of amino acid 191.
It was also reported that various interfaces have influences on the
crystallization of polymorphs [ 11, 121. Recently the effect of additives and
solvents on crystal growth have been explained by analyzing the conformation
of the molecule in crystals, and the interactions of the additive and solvent
molecule with the crystal surface.
However, it has been found that the
dynamic behavior of polymorphs in the crystallization is very dependent on
the various operational conditions. For the selective crystallization of the
polymorphs, the key-controlling factors in crystallization should be known
and, therefore, the crystallization mechanism of the polymorphs may become
clear.
Hence we have investigated the controlling factors in the polymorphic
crystallization of amino acids.
Experimental Details
(i)
Crystallization of L-glutamic acid
L-Glutamic acid was crystallized by rapidly cooling the heated solution of
various concentrations to a set temperature [3]. The concentration change of
solutions was measured, and the slurry was sampled and filtrated during the
crystallization process. The transformation behavior was examined by
measuring the composition change of polymorphs by XRD. The morphology
of the precipitated crystals was observed through a microscope.
(ii) Growth rate measurement using single crystal in aflow system
A single crystal of each /3 and a polymorphs prepared by batch crystallization
were mounted in the growth cell and the growth rates were measured at 298 K
(f0.05 K) in flowing solutions with and without L-Phe [7].The sizes of the
crystals and their morphology were measured using a microscope and
video-TV system, and growth rates calculated from the crystal size change.
M.Kitamura
(iii) Crpstallizatlon of L-histidine
Crystallization was carried out in the aqueous solution and the mixed solution
of water and ethanol in various ratios by the same method as that used in the
L-Glu system [ 9 ] . Concerning the growth rate measurement, the pure
polymorphous crystals were sieved and a cut between 350 and 420 pm was
used. The crystals were suspended in the supersaturated solutions and growth
rates measured from the mass change of the crystals. The polymorphous
composition of the crystals was determined by XRD.
Results and Discussion
Effect of temperature and supersaturation on the crystallization of
L-glutamic acid (L-Glu) polymorphs
L-Glutamic acid (L-Glu) has two polymorphs of a and f3 (both are
and only the lattice parameters
orthorhombic with a space group of P212121
are different) (31. Differential crystallization was carried out to examine the
controlling factors, i.e. the unsaturated solution(s) was rapidly cooled to the
set temperature and then a small amount of crystal was precipitated under
stirring conditions. The polymorphous compositions were analyzed by XRD.
In the crystallization of L-glutamic acid (u and f3 forms) it appeared that the
supersaturation ratio had very little effect on the crystallization ratio of the
L-Glu polymorphs at each temperature between 298 K and 323 K [3]. For
example, at 298 K with the supersaturation ratio range for p crystal (Sg)
between 1.7-4.8, and at 318 K with SB between 1.3-3.0, the influence of the
supersaturation ratio on the polymorphous composition could not be observed.
This may indicate that the “Ostwald’s step rule” [13] cannot be observed in
this crystallization process. Alternatively, the temperature intensively
influenced the crystallization behavior, i.e. at a lower temperature (e.g. 293 K)
only the u form precipitates and with a temperature increase the proportion of
p in the crystals increased as shown in Figure 1. We presume that such a
dependence of the crystallization behavior on temperature is due to the change
in the relative concentration of conformers [141 with temperature.
I
582
Control of Polymorphism in Crystallization of Amino Acid
0
285 290 295 300 305 310 315 320 325
Temp.M
Figure 1. Dependence of a composition in precipitated crystals (X a ) on
crystallization temperature.
Temp.
Conformer a
11
1
.
L
Conformer p
Cluster a
Nucleation
Nuclei
1
Crystal a
Growth
11
Cluster p
1
Nucleation
Nuclei
1
Growth
Crystal p
Figure 2. Conformers and crystallization process.
583
M.Kitamura
The conformers corresponding to each polymorph may aggregate and form
different clusters as shown in Figure 2. The relative concentration of these
clusters may be related to the precipitation ratio of the polymorphs. In
relation to the change of the structure of the cluster, Nyvlt [ 151 measured the
metastable zone width and explained the crystallization behavior of various
hydrates of citric acid, ferrous sulphate and sodium hydrogen phosphate with
the structural change of the clusters in solutions versus temperature.
In the crystallization, the transformation from a to j3 proceeds by the
“solution-mediated mechanism”. The transformation rate is controlled by the
growth rate of the p crystals and also depends on temperature, i.e. the rate at
298 K is much slower than that at 3 18 K. Even when the p crystals were added
to the solution at 298 K, the transformation rate was hardly affected. This
phenomenon indicates that the growth rate of p crystal is very dependent on
temperature (the activation energy of the growth of p crystal is large), and at
298 K the growth rate is very slow.
The crystallization behavior is also influenced by another significant
factor. For example, from stagnant solutions the
crystal tends to crystallize.
This may indicate that the two-dimensional nucleation on the surface of the
crystallizer is advantageous for the nucleation of the p crystal. Furthermore,
at the interface between the air and the solution the p crystal tends to
crystallize preferentially. This may be caused by the template of the
adsorption layer of L-Glu molecule on the interface [ 161.
II Growth mechanism and morphological change of L-Glu polymorphous
crystals
The growth kinetics and morphological change of a and p crystals of L-Glu
were investigated using the single crystal method [17]. The seed crystals of
L-Glu polymorphs (a and p) shown in Figure 3 were prepared through batch
crystallization. The seed crystals were fixed in the flow cell and the linear
growth rate in each direction was measured at 298 K by a microscope. It was
demonstrated that the growth rates of a crystal in the [110],[OIO]and [OOl]
584
Control of Polymorphism in Crystallization of Amino Acid
directions, and that of $ crystal in the [loo] direction appeared not to be
influenced by the diffusion of the solute and were controlled by the surface
reaction process.
From the dependence of the growth rate on the relative supersaturation (a),
the mechanism of growth in all directions of the a crystal appeared to be a
“nuclei-above-nuclei” mechanism as given by Equation (1) below [ 181, rather
than a BCF mechanism [ 191.
where X and Y are constants which depend upon the system. This result was
also supported by the observation of the wavy front of the bunched steps with
the atomic force microscope [20].
The morphological changes of a seed crystals were observed in the growth
process as shown in Figure 4, i.e. the (011) face developed. The
morphological change of the a crystal is due to the difference in the
dependence of the growth rate (G)on the supersaturation (a) between the
(111) and (110) faces as shown in Figure 5 . This indicates the important
contribution of the kinetic process to the morphological change.
Dependence of the growth rate of the (1 0 1) face of flcrystal on the relative
supersaturation (a) is shown in Figure 6. From the kinetic data, the growth
mechanism of the (101) face of the p crystals is also considered to be the
“nuclei-above-nuclei” mechanism. The growth rate of the (1 11) face of the a
crystal is several times that of the growth rate of the (101) face of at the
same supersaturation. This observation also corresponds to the preferential
crystallization of a at 298 K. Furthermore, the ratio of the growth rate of p
to that of a tends to increase with an increase in the supersaturation as
determined by:
G(lOl)~/G(lll),=
, 0.22 exp(-0.14/0)
(2)
585
M.Kitamura
(111)
Flow
A1
A3
1 D2
(a)
Figure 3. Seed crystals of L-Glu polymorphs: (a) a ;(b) p
Figure 4. Morphological change of a crystal in pure system.
586
Control of Polymorphism in Crysallization of Amino Acid
0
0.1
0.3
0.2
0.5
0.b
0.1
0.6
u c-I
Figure 5. Comparison of the growth rate (G) of a crystal between ( I I I ) and
(011) face.
0
?
O
.
0.0
O
L .
0.1
'
0.2
.
'
.
0.3
~
.
0.4
~
.
0.5
B
.
0.1
S
.
0.1
u [-I
Figure 6. Dependence of the growth rate of (101) face of Bcrystal on the
relative supersaturation (u).
58 7
M.Kitamura
The parameters of the “nuclei-above-nuclei” model for the growth rate in
each direction of both polymorphs were given by the least squares method.
The edge free energy (y) was also calculated from the parameter Y given by:
Y = (Z/ 3 ) ( y /kT)’
(3 1
The edge free energy of the (1 0 1) face of fl is relatively larger than that of
a crystals (( 111) and (001) faces). This observation is related to the solubility
difference, i.e. the edge free energy of the stable form fl with a low solubility
is higher than the metastable form a with a high solubility. The higher
growth rate of a may be due to the large kinetic effects and the low edge free
energy of a.
III Crystaliization of L-histidine (L-His) polymorphs compared to L-Glu
L-Histidine (L-His) has two polymorphs of orthorhombic (P212121)and
monoclinic (P21)which are denoted as the A and B forms, respectively [21].
The solubility measurement (at 293-330K) indicated that the stable phase is
the A form [22].It was observed that the polymorphs crystallize with the same
proportion (fraction of A, XA= 0.4-0.6) regardless of the concentration range
(C)from 0.34 to 0.48 mol/l, corresponding to the supersaturation ratio range
in respect to the A form (SA) from 1.34 to 1.90 as shown in Figure 7. This
result also indicates that Ostwald’s step rule cannot be observed in the
crystallization of L-His. However, the dependence of XA on temperature was
found to be very small as shown in Figure 8, i.e. the tendency is very different
from that in the case of L-Glu.
Furthermore, the seed effect on
crystallization behavior was examined. The seed crystals of each polymorph
(1 mg, 105-149pm) were added to the solution (50 ml) just after the solution
attained the set temperature during the crystallization before the primary
nucleation occurred. It appeared that neither the A nor B seeds had any
effect on the crystallization behavior of the polymorphs (see Figure 7). For the
crystallization of L-Glu, the seed effect was observed. These differences of
the seed effect between the L-Glu and L-His polymorphs may be related to the
588
Control of Polymorphism in Crystallizationof Amino Acid
1.o
Temp. 293K
0 :
0.8
0 :
no seeds
A
B
)
seeds
n
A
0.6
4
x
0.4
0.2
0
0.35
0.45
0.40
C Emo1/11
Figure 7. Dependence of composition of A form in L-His crystals (Xd on the
concentration (C) and seed efsect.
-1
(b)
0.8
0.6
-
0.4
-
0.2
-
280
GHls
T
-7
1
285
J
290
295 300
Temp. [Kl
305
310
315
Figure 8. Dependence of A composition in precipitated crystals (XJ
on
crystallization temperature.
589
M.Kitamura
t [mid
--*:
240
---o-: 480
-.
: 1000
n
E 0.4
a
\
3
U
0.2
0
200
400
600
800
bml
Figure 9. Change in crystal size distribution in the transformation process by
solution-mediated mechanism.
VOL I-]
Figure 10. Dependence of A composition (XJ in crystals on ethanol
composition (VUL).
590
Control of Polymorphism in Cytallization of Amino Acid
different physical properties between these amino acid molecules. When the
solubility difference between the polymorphs of each amino acid is compared,
it is much smaller in the case of L-histidine (44%) than in the case of
L-glutamic acid (2548%). This is the cause of the slow transformation rate of
L-His polymorphs when compared to that of L-Glu polymorphs. Such
behavior may be attributed to the differences of the free energy of the
molecule and the crystal structures between each of the polymorphs. L-His
has a bulky imidazole group and the number of carbons is smaller than L-Glu,
while the conformational difference between A and B polymorphs is very
small [21], in comparison with that for L-Glu polymorphs. Hence in the case
of L-His, the activation energy for the exchange between the conformer
should be very small, and the conformers corresponding to A and B forms in
solutions may be present at about the same probability.
The transformation by the “solution-mediated mechanism” also occurs
between the L-His polymorphs. During crystallization a change in the crystal
size distribution (CSD) was observed as shown in Figure 9 . For example, as
shown in Figure 8, two peaks were observed in CSD and the peak for the
small size crystals increased with time, whereas the peak of the large size
crystals decreased. This change in CSD is due to the “solution-mediated
transformation”, i.e. the metastable B form with a large size dissolves and the
stable A form nucleates and grows.
IV Effect of solvent composition on L-His crystallization
When L-His was crystallized from the mixture of ethanol and water, the effect
of the solvent composition on the crystallization of the polymorphs was
observed [9]. Figure 10 shows the relationship between the fraction of A
form in a precipitate (X,) obtained by the differential crystallization and the
volume fraction of ethanol (VOL) at each temperature. It can be seen that the
value of XA is not influenced by the ethanol composition at a low VOL,
however, it decreases rapidly at a VOL larger than about 0.2 and finally pure B
crystals precipitate. With a temperature decrease, the increase of the amount of
B form due to ethanol seems to be accelerated. Dependence of the solubility
591
IU.
Kitamura
(C') on the solution composition at each temperature is shown in Figure 1 1. It
can be seen that the solubility difference decreases with the increase of the
ethanol fraction (VOL). However, this tendency cannot explain the
crystallization behavior seen in Figure 10.
The effect of the solvent composition on the growth rate was examined at
293 K by measuring the mass change of the polymorphous seed crystals which
were suspended in the supersaturated solutions. The growth rate (G) was
calculated from the mass change of the seed crystals, assuming a spherical
shape. It appeared that the growth rate of B form is larger than that of A at the
same supersaturation level for every VOL. However, when the growth rate of
A and B form is compared at the same concentration, they appear to take very
similar values at zero of VOL as shown in Figure 12(a). With the increase of
VOL up to 0.4, the difference of the growth rate increased as seen in Figure
12(b). This result indicates that ethanol suppresses the growth rates of A
selectively at an ethanol composition larger than 0.2 [9]. In comparison with
the crystallization behavior in Figure 10, it is expected that not only the growth
but also the nucleation of A is hindered by ethanol. It is presumed that the
increase of VOL may make the concentration of the conformer corresponding
to B increase, while the desolvation energy of B may also get smaller in
comparison with A. This may result in the preferential nucleation and growth
of B. The solvent effect seems to increase with a decreasing temperature as
shown in Figure 10. This may be due to the decrease of the molecular motion
with temperature.
V
Effect of additives on L-Glu crystallization
Various amino acids influence the Crystallization of L-Glu polyrnorphs, e.g.
L-valine and L-leucine isomers inhibit the crystallization rate of L-Glu and
are also included in L-Glu crystals in the course of the crystallization process
1231. The effect of L-Phe on the nucleation and the growth of L-Glu is
relatively large. Figure 13 shows the composition change of a crystal in the
course of the crystallization at 318 K [24]. It can be seen that with an increase
592
Control of Polymorphism in Cgstallization of Amino Acid
Temp
Cryrtols
A
313K (+ : B
- & :
0
0.1
0.2
0.3
293K
(zj
283K
( gi
01;
0.5
0.6
$
0.7
VOL 1-3
Figure 11. Dependence of solubility of L-His polymorphs on ethanol
composition.
Temp. 293M
voL= 0
4
4 :A
12
C Cmolill
C tmollll
Figure 12. Relationship between growth rate of L-His polymorphs and
concentrations at: (a) 0 of VOL; and (b) 0.4 of VOL.
593
M. Kitamura
1.0
I
Y
’0.5
4: 0
0.5
+:
10
20
30
00
50
60
70
80
90
1 [hl
Figure 13. Effect of L-Phe concentration on the a composition in precipitated
crystals (y) at 318 K.
.
.
L
c d.9X10 dmovl
,o
‘0°
P -5
0:Al
0:Al
9
‘
9‘
O:AZ
@:A3
A:B1
I
I
,A
0’
I
Y
/
/
@-*A
.O
,o‘
,
0
I
t
[mln]
t
[min]
Figure 14. Crystal size change (AL) with time (t) at L-Phe concentrations o j
(a) 7 . 7 x 10-4mol/l; and (b) 1.3 x lo” mol/l.
594
Control of Polymorphism in Crystallization of Amino Acid
of L-Phe concentration, the nucleation of the
rate, i.e. the growth rate of
p crystal and the transformation
p crystal, is suppressed. This result also means that
the growth of a crystals is hindered by L-Phe, because the crystallization rate
is retarded by the increasing L-Phe concentration.
To examine the difference in the effect of L-Phe on the growth kinetics and
the morphology of L-Glu polymorphs, the single crystal method in a flow
system was used and the effect of L-Phe on the growth kinetics was compared
between the polymorphs [7]. The seed crystals of L-Glu polymorphs (a and
p)
are shown in Figures 3(a) and (b). It was observed in the growth rate
measurement of a crystals that the growth rate in the [OOl]direction (D) is not
influenced by L-Phe. However growth in the direction parallel to the (001)
main face (Al,A2, A3 and Bl) is retarded by L-Phe. In pure solutions and at
low concentrations of L-Phe (less than 7.7 x
mol/l), the growth of the
seed crystals in each direction (Al,A2, A3 and B1) was very linear in time
for both polymorphs (see Figure 14a). However, with an increase of the L-Phe
concentration, the growth became irregular and the growth rate tended to
fluctuate with time (see Figure 14b). Furthermore, with the addition of L-Phe
in the solution, the intensive morphological change appeared in the case of the
a crystal (see Figure 15), i.e. the growth rate in the [ 1 1 11 direction was
suppressed and the new (110) face appeared, while the small (011) face
disappeared. This means that L-Phe adsorbs selectively on the (1 10) face and
inhibits the growth of that face in preference to the (OOl), (111) and (011)
faces under this condition. From the crystallographic data it can be seen that
the carboxylic acid group is rich in the (001) face (see Figure 16). Thus, it
may be assumed that L-Phe cannot adsorb on the (001) face because of
repulsion from the carboxylic acid group. However, discrimination of the
interaction with L-Phe among the (110), (111) and (011) faces is difficult.
Davey [ 5 ] investigated the effect of different 1,5 dicarboxylic acid compounds
on the morphological change of L-Glu with a conformational analysis. He
observed that the (1 1 1) face of L-Glu is predominant with glutaric acid while
the (1 10) face appears with transglutaconic and trimesic acids. In our previous
work with batch crystallization, it was observed that even when using the
same additive, L-Phe, the (1 11) face becomes predominant. This indicates the
595
M Kitamura
Figure 15. Morphological change
Figure 16. Molecular arrangement in
of a crystal in the presence
the surface of (OOI), (I I I ) and (I 10)
of L-Phe.
faces of a crystal.
1.4
-=
h
!
I
1.2
-
0.8
-
0.4
-
0.2
0.2
C = 0.003 ml/l
(u-O.SO0)
-
Calculatrd
0.4
0.6
~ ~ ~ 1 tn~i/ii
0 3
0.8
cp'
Figure 17. Growth rate dependence of L-Glu polymorphs (G) on
concentrations (Cp) of L-Phe; a. a-crystal (I 10) face; b. /I-crystal (I 01) face.
596
Control of Polymorphism in Crystallization of Amino Acid
importance of the kinetics and the crystallization conditions on the
morphological change.
Figure 17(a) shows the relationship between the growth rate of the (1 10)
face and L-Phe concentration. With L-Phe concentration (Cp), the increase of
the growth rate of the (1 10) face of the a crystal declined, and finally stopped
at the critical concentration, Cp* (1.7 x lo-’ mol/l). However, the growth of
p crystal, which is the fast growing face of the p crystal,
was also hindered and the growth rate of the (101) face of p decreased with
the (101) face of the
the L-Phe concentration as shown in Figure 17(b). It appears that the critical
concentration of L-Phe, Cp* for the (1 10) face of a is about twice that for the
(101) face of
p (0.7 x
lo” mol/l) at almost the same L-Glu concentrations (C).
These results demonstrate the preferential inhibition of the growth of p.
The dependence of the growth rates on the concentration of the additive
(Cp) can be expressed by Equation (4) below for both polymorphs, using the
growth model of a curved step and the adsorption density of the additive [7].
The observation of a ‘cluster of grapes’ on the crystal surface with an atomic
force microscopy supports the model assumption that the adsorption of L-Phe
defines the advancing steps [ 181.
G = G,[l- 2pCd”’]
Pc
(4)
==
P
where Go is growth rate in the pure solution; p c is the critical radius; d is the
adsorption density; y is the edge free energy; a is the lattice constant; k is
the Boltzmann constant; and T the temperature (K).
To analyze the adsorption behavior of the additives, the Langmuir-type
model was applied. However, it was clear that in both cases of a and p
polymorphs the Langmuir-type isotherm could not be applied to the
experimental results, and the Freundlich-type isotherm equation was
applicable. Therefore, the adsorption density (d) is expressed by:
d = KCpn
where K and n are the constants in the Freundlich-type equation.
597
M.Kitamura
The calculated values of the growth rates by the least squares method using
Equations (4) and (6) are shown in Figures 17(a) and (b) by the solid lines.
These results indicate that the effect of the additives is not only due to the
molecular interaction between the additive molecule and the crystal surface,
but the kinetic process also contributes significantly to the effect.
The adsorption density can be correlated with the distance between the
neighboring adsorbed additive molecules ( e ) by:
d=F
1
(7)
The dependence of the growth rate of the (1 10) face of a crystals on the
relative supersaturation ( 0 ) and adsorption density is given by:
Values of (Go-G)/Go are plotted against l/a at various additive
concentrations for a form in Figure 18, showing an approximately linear
relationship. For the p form, a similar relationship was obtained. The slope
of a line corresponds to the value of B&, and the linear relationship implies
that the density (d) is almost a constant and is independent of supersaturation.
For the practical use of additives in the selective crystallization of
polymorphs, then the supersaturation and the concentration of additives
should be controlled simultaneously. If the growth of only p form is
completely inhibited, then the value of 2p, should be between the t values
of each polymorph (!.
and .!B ) and the following equations apply:
B
B
-<u<la
e,
Hence the supersaturation (a) in the crystallization can be determined for each
Cp value from these equations.
598
Control of Polymorphism in Crystallization of Amino Acid
I
2
4
6
8
l/u
10
12
14
[-I
Figure 18. Plot of (Go-G)/Goagainst 1 / tfor
~ (110) face of a crystal.
I
Solubility of polymorphs
1
I
0
Control of crystallivltion of
polymorphs
Primarv factor
Supersaturation
*Temperature
*Coolingrate
Stirring rate
Mixing rate of reactant solutions
'Seed crystals
Nucleation
0 Growth
0 Transformation
I
Secondarv factor
-*Additives
Solvent
*Interface
PH
I
Figure 19. Schematic diagram of controlling factors in crystallization of
polymorphs.
599
M.Kitamura
VI Controllingfactors in crystallization of polymorphs
Using the preceding results we classified the controlling factors for the
crystallization of polymorphs as shown in Figure 19. The most influential
factors were classified as the primary factors, these were both supersaturation
and temperature. In addition, the cooling rate may be part of the primary
factors. However, in the cooling crystallization, changes in the temperature
and supersaturation occur simultaneously. Therefore, the effect of the
supersaturation and temperature should be examined separately. In the
reactive crystallization, the mixing rates of the solutions appeared to be very
important [25]. Factors due to the external effects such as solvents, additives,
interface and pH are grouped in the secondary factors. The effects of the
additive is quite complex and the kinetic effect should be considered as well
as the molecular structures [7].
The solubility of each polymorph is not the main operational factor,
however, the supersaturation of each polymorph is based upon the solubility.
Furthermore, the relative thermodynamic stability and the direction of the
transformation between the polymorphs can be expected from the solubility of
polymorphs.
Conclusions
We have shown that the effects of supersaturation (Ostwald's step rule) were
rarely observed in the systems (L-giutamic acid (a, p) and L-histidine (A, B)).
The temperature effect was significant for L-glutamic acid polymorphs,
however, no temperature effect was observed in the crystallization of
L-histidine polymorphs. These different temperature effects may be related to
differences in the molecular conformation between the polymorphs. The
growth mechanism of L-glutamic acid polymorphs appeared to be almost
identical, however, the dependence of the growth rate on the degree of
supersaturation was different. The influential factors, such as temperature and
supersaturation, can be regarded as the primary factors in polymorphic
crystallization. External factors such as solvents and additives also have an
influence on polymorphic crystallization. The solvent effect was studied by
600
Control of Polymorphism in Crystallization of Amino Acid
the influence of ethanol composition on the crystallization of L-His
polymorphs (A and B). It was shown that the effect is due to the suppression
of the nucleation and the growth rate of A form with an increase in the ethanol
composition. The effect of amino acids as an additive on the crystallization of
L-glutamic acid was examined. In particular, the effects of L-Phenylalanine
on the growth rate and morphology of L-glutamic acid polymorphs were
examined using the single crystal method. Equations are presented which
describe the relationship between the additive concentration and the growth
rate of each polymorph. The importance of the kinetics of the crystallization
for the control of the polymorphic crystallization was demonstrated. The
calculation of the supersaturation needed for the control of the selective
crystallization of the polymorph was also determined. From these results the
controlling factors for the crystallization of polymorphs have been classified
in order to clarify their complex interrelationship.
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Received: 25 July 2002; Accepted after revision: 20 July 2003.
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