Journal of Chemical Engineering of Japan, Vol. 52, No. 7, pp.

599–604, 2019 Research Paper

Control of Reaction Crystallization of Organic Compounds

Using the Supersaturation Profile
Eriko Sato1,2, Yuichiro Seki 2 and Hiroshi Takiyama2
1
Research and Development Department, Otsuka Chemical India,
SP-3 10&11 RIICO Industrial Area Keshwana Rajpoot Kotputli Jaipur Rajasthan, India
2
Department of Chemical Engineering, Tokyo University of Agriculture and Technology (TUAT),
24-16 Nakacho-2, Koganei-shi, Tokyo 184-8588, Japan

Keywords: Reaction Crystallization, pH, Supersaturation Profile, CSD, Morphology

Neutralization reaction crystallization is useful for manufacturing drugs that require high bioavailability (i.e., high solu-
bility). Because drug crystals must be of high quality, with the optimal form and particle size, the development of proce-
dures that can produce high quality crystals by reaction crystallization is important. In cooling crystallization, analysis of
the supersaturation profile (SSP) is an effective way to improve the crystal quality. SSP analysis is also important in reac-
tion crystallization. However, the changes in the operation parameters (e.g., pH) necessary for crystallization strongly
depend on the deposition of the crystals. Thus, solution pH also changes with deposition of the crystals. The purpose of
this study is to propose an optimal crystallization point for the improvement of crystal quality through SSP analysis in
reaction crystallization. The experimental system involved the reaction of hydrochloric acid and L-arginine to crystallize
L-arginine hydrochloride monohydrate. The SSP was computed using HPLC and a pH meter. The relationship among the
amount of feed added, crystal size distribution (CSD), and the crystal morphology was investigated through SSP analysis.
Control of minute crystals was found to be crucial for CSD improvement. Moreover, operation at a neutral pH and the use
of seed crystals were found to effectively inhibit the formation of minute crystals. Furthermore, operation at basic pH ef-
fectively produced good crystal morphology. Finally, using these results to modulate the addition technique in the reac-
tion crystallization process, quality crystals with the desired CSD and morphology have been produced.

controlled particle size and crystal purity without adversely

Introduction
Reaction crystallization is a type of crystallization involv-
ing chemical reaction (Torbacke and Rasmuson, 2001; Lu
and Wang, 2006; Su and Chiu, 2016). In reaction crystal-
lization involving a neutralization reaction, highly soluble
crystal salts can be precipitated by reacting an acid and a
base (Zumstein and Rousseau, 1989; Gunnam et al., 2018).
Because high bioavailability is desirable in pharmaceuti-
cals, the ability to increase solubility using neutralization
reactions is useful in precipitating salts for pharmaceuticals
(Thomas et al., 2017). Therefore, crystallization via neutral-
ization reaction is often adopted in pharmaceutical manu-
facturing.
The pharmaceutical industry also requires high qual-
ity products with a monodisperse crystal size distribution
(CSD) and a low aspect ratio morphology (Christian et al.,
2000; Yang et al., 2015). However, in reaction crystalliza-
tion, the dispersion coefficient tends to be large, and crystal
particles with a wide CSD are often precipitated (Mikami
et al., 2010). Additionally, organic crystals often exhibit a
high aspect ratio, with plate-like or needle-like crystals tend-
ing to be produced (Roelands et al., 2007; Tung et al., 2009).
Thus, there is a real need to develop a high-quality method
to control reaction crystallization and produce crystals with
Received on January 28, 2019; accepted on April 19, 2019
DOI: 10.1252/jcej.19we017
Correspondence concerning this article should be addressed to E. Sato
(E-mail address: Sato.Eriko@otsuka.jp).
affecting its productivity (Claassen and Sandenbergh, 2007;
Kim et al., 2011). Recently, various studies of batch cooling
crystallization have been conducted to determine meth-
ods to achieve optimal crystal quality. Researchers have
attempted to classify the relationship between the crystal-
lization method and the crystal quality using the concept
of the supersaturation profile (SSP) (Cheow et al., 2014; Liu
et al., 2016). This profile represents how the supersaturation
changes over time (Mackellar et al., 1994). Applying the
concept of SSP to reaction crystallization has the potential
to improve the quality of the products (Sazaki et al., 1994;
Utomo et al., 2010). However, in reaction crystallization, the
change in solubility depends not only on the temperature,
but also on the pH (Alatalo et al., 2010). The solution pH
is also changed by the deposition of the crystals in reaction
crystallization. Thus, the purpose of this study is to investi-
gate the relationship between the SSP and the properties of
the crystals (CV and aspect ratio) and to propose an optimal
crystallization point based on the analysis of the SSP in reac-
tion crystallization.
1. Experimental
1.1 Calculation of the SSP
As shown in Scheme 1, L-ArgHCl·H2O was crystallized
by reacting the reagents L-Arg (Ajinomoto Co., Ltd.) and
6 mol/L HCl (FUJIFILM Wako Pure Chemical Industries,
Ltd.). The concentration C* of the product L-ArgHCl·H2O
was calculated from the solubility curve in Figure 1 using

Vol. 52  No.©7 2019 

Copyright 2019The Society of Chemical Engineers, Japan 599

Scheme 1 Scheme of the reaction crystallization of L-ArgHCl·H2O
Fig. 1 Solubility curve of L-ArgHCl·H2O and the three pH regions:
the (a) acidic region, (b) neutral region, and (c) basic region
Eq. (1).
C*= 90.34 × (1+10(1.66 pH) )
The value of the concentration C of L-ArgHCl was mea-
0
sured using high performance liquid chromatography
(HPLC) (LC 20 AT, Shimazu Corp.) at a wavelength of
210 nm. The pH value was measured using a pH meter
(DKK-TOA Co., Ltd.). The C0 value was determined at each
pH level by sampling 1.0 mL of the solution and diluting the
sample to 100 mL with water. In order to accurately quantify
C0, fumaric acid was used as an internal standard. Then, the
supersaturation σ was estimated using C* and C0 as de-
scribed in Eq. (2).
σ = (C 0  C *) / C *
1.2 Crystallization experiment using the SSP
The reagent L-Arg was added to 6 mol/L HCl (109.8 g,
0.60 mol) in a 300 mL jacketed crystallizer, and the mix-
ture was agitated at 400 rpm by a four-bladed propeller.
The solution temperature was controlled at 300 K using a
precision thermostatic chamber. After filtration and dry-
ing, the crystals were observed using a scanning electron
microscope (SEM) (JSM-6510, JEOL Ltd.), and the crystal
size was estimated at the Krummbein diameter. The circle
in Figure 1 indicates the main area of focus, i.e., the region
in which the solubility did not change. Within the marked
area, there are three distinct regions: (a) the acidic region,
(b) neutral region, and (c) basic region. In each region, a dif-
ferent amount of L-Arg was added: (a) 101.0 g, 0.58 mol, (b)
105.2 g, 0.60 mol, and (c) 125.0 g, 0.72 mol.
The solution pH was adjusted via the mixing ratio of the
two feed materials. The pH of the saturated solution was
determined from the concentration of the excess material
600
using the Henderson–Hasselbalch equation, shown below as
Eqs. (3) and (4), for L-ArgHCl·H2O. Equation (3) represents
the pH change from the acidic region to the neutral region,
and Eq. (4) represents the pH change from the neutral re-
gion to the basic region.
pH = 3.61  0.65 × lnCHCl (3)
pH = 7.29 + 0.44 × lnCL-Arg (4)
SEM observations were conducted to examine the crystal
quality, CSD, and crystal morphology within each of these
three regions. Additionally, in this study, a metastable anhy-
drate form and a stable monohydrate form were observed.
As the crystallization was assumed to proceed in the sus-
pension according to Ostwald’s step rule, we considered
that first, crystallization of the anhydrate occurred, followed
by transformation to the monohydrate. Each sample was
identified using X-ray powder diffraction analysis (XRPD)
(Ultima IV, CuKα radiation, Rigaku Corp.).
1.3 Measurement of the single crystal growth rate
A jacketed cell with a volume of 20 mL was used in
this experiment. The cell was filled with a supersaturated
solution or unsaturated solution in which the supersatura-
tion and pH were chosen. The supersaturated or unsatu-
(1)
rated solution was prepared in a 200 mL flask by weight-
ing out L-Arg, 6 mol/L HCl, and ion-exchanged water.
L-ArgHCl·H2O was immersed in the conditioning solution,
and the growth rate was observed. During the experiment,
300 K water was allowed to circulate through the jacket.
2. Results and Discussion
2.1 Nucleation characteristics in the acidic region
The SSP profile of region (a) is shown in Figure 2, and the
resulting CSD is shown in Figure 3 and Table 1. The super-
saturation is indicated by the gray circles in Figure 2, and
(2)
decreased drastically with time. In the acidic region, because
HCl was present in excess relative to L-Arg, the equilibrium
after the neutralization reaction was acidic, and the pH de-
creased. At the same time, as shown in Figure 3, the CSD
also exhibited drastic changes suggesting that the sudden
decrease of the supersaturation was related to the nucleation
of a large number of fine particles. The data suggested that
aggregation occurred after 180 min because the mean length
increased, while the CV value was almost unchanged.
The crystal morphology was variable, as shown in Fig-
ure 4. Moreover, the CV eventually increased to 110%,
which further suggests that the nucleation of fine particles
negatively affected the CSD. Additionally, the aspect ratio
reached 2.24, as shown in Figure 5 and Table 1; i.e., the long
axis was about twice as long as the short axis. For this rea-
son, it seemed that if nucleation could be inhibited, it might
improve the CSD.
2.2 Effects of pH on the crystal growth rate
Because the crystal quality was unfavorable in region
Journal of Chemical Engineering of Japan
 Fig. 2 Supersaturation profile in the acidic region Fig. 5 Aspect ratio of the L-ArgHCl·H2O crystals in the acidic region

Fig. 3 CSD over time in the acidic region

Fig. 4 L-ArgHCl·H2O crystals in the acidic region

Table 1 Quality of the product crystals

pH area LN [µm] CV [%] Aspect ratio [—]

Acidic 123 110 2.24 Fig. 6 Supersaturation profile for (a) neutral and (b) basic conditions
Neutral 111 41 1.56
Basic 89 53 1.07
L-ArgHCl·H2O precipitated predominantly, but the crystal
morphology was different. The crystal growth rates of L-
(a), the crystal growth rates in the other regions were in- ArgHCl·H2O at σ=0.2 and pH 7.5 were 0.092 µm/s in re-
vestigated. The results seemed to suggest that the crystal gion (b) and 0.057 µm/s at pH 8.5 in region (c), as shown in
growth was dependent on the pH, and that consequently, Figure 7. Not only was the crystal growth rate greater in the
the crystal size distribution was affected as well. The SSP of neutral region, but, as shown in Table 1, the CV values were
region (b) and region (c) during L-Arg addition are shown also better, suggesting that nucleation may have been inhib-
in Figure 6(a) and (b). In region (b) and (c), the super- ited. In addition, as shown in Figure 8(a), the aspect ratio of
saturation decreased gradually during the process, in which region (b) was better than that of region (a). Furthermore,

Vol. 52  No. 7  2019 601

 Fig. 7 Growth rate as a function of pH value at σ=0.2
Fig. 8 Aspect ratio of L-ArgHCl·H2O crystals produced in the (a)
neutral region and (b) basic region
although the aspect ratio in region (c) was smaller than
that in region (b), as shown in Figure 8(b), the CV value of
the crystal morphology was much better in region (b). The
quality of the crystals produced by L-Arg addition in region
(b) and region (c) is shown in Table 1. The CV was 41% in
region (b), whereas it was 53% in (c). As seen in Figure 9(a)
and (b), the crystal dispersion was worse for region (c).
602
Fig. 9 L-ArgHCl·H2O crystals produced in (a) neutral and (b) basic
conditions
Fig. 10 Improvements in the crystal quality
2.3 Reaction crystallization using pH modulation
The above results provide insight into a method for im-
proving both the CSD and crystal morphology simultane-
ously. In terms of pH, it is clear that working in the neutral
region improves the CSD, while the basic region favors
improved crystal morphology, as shown in Figure 10. The
challenge was to devise a method to improve both qualities
at the same time. To this end, an internal seeding method
was examined. The initial idea was to precipitate a small
internal seed crystal in the neutral region, and then to use
this low aspect ratio crystal as an internal seed in the basic
region to comprehensively improve the crystal quality.
Then, a method involving the modulation of the addi-
tion of L-Arg was conducted. First, an internal seed that
appeared at maximum supersaturation was produced with a
low aspect ratio in the neutral region (σ=0.592), and then,
a supersaturation very similar to that of the neutral region
(σ=0.670) was obtained in the basic region, as shown in
Figure 11. The pH and temperature profiles are shown in
Figure 12. One feature of this method is that high reaction
heat is generated when the system is moved to the basic
Journal of Chemical Engineering of Japan
 Fig. 11 Strategy of the internal seeding method
Fig. 12 pH-temperature profile during pH modulation
region.
Next, the quality of the crystals from the stages before
and after the modulation procedure was compared. Images
of the crystals are shown in Figure 13(a) and (b), and the
crystal properties are listed in Table 2. The results confirmed
that the modulation procedure resulted in a more monodis-
perse CSD. This was attributed to the fact that high reaction
heat was generated when the seed was applied to the basic
region, and that an unsaturated condition was achieved,
leading to the dissolution of excess fine particles. The aspect
ratio of the crystals was also reduced by operating in the
basic region. From these results, it was found that not only
did applying the modulation procedure improve the aspect
ratio, but also that the heat of reaction contributed to the
improvement of the CSD. Thus, comprehensive improve-
ment of crystal quality appears to be a possibility.
Based on these results, modulation by material addi-
tion was found to greatly improve both the CV and aspect
ratio compared with the monotonous procedure. Therefore,
by taking the nucleation characteristics and crystal growth
characteristics into account during the process, a monodis-
perse CSD and low aspect ratio crystal morphology can be
achieved at the same time.
Vol. 52  No. 7  2019
Fig. 13 L-ArgHCl·H2O crystals produced by pH modulation: (a) in-
ternal seeds and (b) product
Table 2 Data regarding the CSD and aspect ratio
Status LN [µm] CV [%] Aspect ratio [—]
Internal seeds 100 38 1.65
Product 142 34 1.38
Conclusion
The reaction crystallization of L-Arg and HCl to precipi-
tate L-ArgHCl·H2O was considered. The SSP analysis was
carried out, the relationship between the reaction crystal-
lization process and crystal quality was determined, and the
following conclusions were obtained.
1. When L-Arg was added monotonically in the acidic re-
gion, SSP and CSD analyses simultaneously revealed the
existence of a time point at which fine particles nucle-
ated rapidly during the crystallization. Because the CSD
was worsened by the sudden nucleation of fine particles,
the nucleation of these fine particles must be controlled
in order to improve the CSD.
2. Even at the same supersaturation, the CSD and crystal
morphology were different at the acidic, neutral, and
basic pH levels. A closer examination of the effects of
pH on crystal growth revealed that the crystal growth
rate was fastest in the neutral region, and that the CSD
was effectively improved by the inhibition of fine par-
ticles. In the basic pH region, because the crystal growth
603
 rate of the long and short axes were almost the same,
low aspect ratio crystals could be obtained, and the crys-
tal morphology was effectively improved.
3. Based on the results of the analyses, an procedure in-
volving modulating the addition of L-Arg was devel-
oped. An internal seed was produced to inhibit fine par-
ticles, and was grown in the low aspect ratio conditions
in the modulated method. As a result, a monodisperse
CV of 34.1% was achieved, along with a low aspect ratio
of 1.38.
In conclusion, by analyzing the SSP of reaction crystal-
lization, the influence of the pH and nucleation characteris-
tics of the fine particles on the crystal quality was revealed.
Based on these results, a modulated material addition meth-
od was developed, and both the CSD and crystal morphol-
ogy were improved. This investigation hints at a method that
may be able to improve the quality of products manufac-
tured by neutralization reaction crystallization.
Nomenclature
C0 = concentration of L-ArgHCl solution [g/100 g H2O]
C* = concentration of L-ArgHCl·H2O that is calculated by
calibration curve as shown in Figure 1 [g/100 g H2O]
CHCl = concentration of excess HCl [g/100 g H2O]
CL-Arg = concentration of excess L-Arg [g/100 g H2O]
CV = coefficient of variation of crystalline particles [%]
LN = number average median diameter of crystal [µm]
‹Greek letters›
σ = degree of supersaturation [—]
σmax = maximum degree of supersaturation [—]
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