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Metastable crystal growth of acetaminophen using solution-mediated phase transformation

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2017 Appl. Phys. Express 10 015501
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Applied Physics Express 10, 015501 (2017)

https://doi.org/10.7567/APEX.10.015501

Metastable crystal growth of acetaminophen

using solution-mediated phase transformation
Yoichiro Mori1, Mihoko Maruyama2,3*, Yoshinori Takahashi1,4, Hiroshi Y. Yoshikawa1,5, Shino Okada4,
Hiroaki Adachi1,4, Shigeru Sugiyama6, Kazufumi Takano2,4, Satoshi Murakami4,7, Hiroyoshi Matsumura4,8,
Tsuyoshi Inoue1,4, Masashi Yoshimura1, and Yusuke Mori1,4
1

Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan

Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto 606-8522, Japan
3
Institute of Low Temperature Science, Hokkaido University, Sapporo 060-0819, Japan
4
SOSHO Inc., Suita, Osaka 565-0871, Japan
5
Department of Chemistry, Saitama University, Saitama 338-8570, Japan
6
Graduate School of Science, Osaka University, Suita, Osaka 565-0871, Japan
7
Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan
8
Department of Biotechnology, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan
2

*E-mail: maruyama@cryst.eei.eng.osaka-u.ac.jp
Received November 12, 2016; accepted November 21, 2016; published online December 13, 2016
We report a new method of obtaining the metastable phase form II crystals of acetaminophen. Solution-mediated phase transformation (SMPT)
from trihydrate into form II is utilized to obtain form II crystals. SMPT is triggered by seeding form II crystals into a saturated solution including
trihydrate crystals, which are less stable than form II crystals. Form II seed crystals gradually grew at the expense of the dissolving trihydrate
crystals, and nally, all the trihydrate crystals in solution were transformed into form II crystals in about 4 h. Thus, we conclude that SMPT is
effective for the production of form II crystals. 2017 The Japan Society of Applied Physics

olymorphism control is a very important issue in the

pharmaceutical industry, because drug properties
such as stability, solubility, processability, and bioavailability are greatly inuenced by polymorphism.1) In
general, to ensure consistent product quality and performance
during storage, the most thermodynamically stable phase is
used in commercial formulations.2) However, the most stable
phase shows the lowest solubility.3) In addition, poorly watersoluble drug candidates are becoming more prevalent.4) For
these reasons, there is now growing interest in the use of a
metastable phase to improve properties such as solubility.
However, it is dicult to obtain a metastable phase selectively. If stable and metastable phases nucleate and exist in
solution at the same time, the metastable phase will readily
transform into the stable phase.5,6) This general phenomenon
makes it dicult to obtain a stable metastable phase.
The purpose of this study was to develop a technology for
obtaining the metastable phase of pharmaceutical compounds. Acetaminophen (paracetamol), a widely used antipyretic and analgesic drug, was used as a model compound.
Acetaminophen has three anhydrous polymorphs: form I
(monoclinic, stable),7) form II (orthorhombic, metastable),8)
and form III (orthorhombic, metastable).9,10) In addition,
three hydrates (mono-,11) di-,12) and trihydrates13,14)) have
been reported. Form I is used in commercial formulations,
while form II has signicant advantages over form I in terms
of solubility and compressibility.15,16) Form III is extremely
unstable and can be crystallized only under limited conditions.6,17) Therefore, form II is now expected to be used in
formulations. Recently, we have reported that form II can be
selectively crystallized by ultrasonic irradiation under smallscale conditions (0.8 ml).18) However, this method is dicult
to scale up because ultrasonic waves propagating in the
sample will vary with the shape and size of the sample
container. Thus, there is a need of a new method of obtaining
form II, which can be scaled up. Here, solution-mediated
phase transformation (SMPT) was utilized to obtain form II.
SMPT is the transformation of a less stable polymorph

Fig. 1. New route to obtain acetaminophen form II.

(higher solubility) into a more stable polymorph (lower

solubility) through solution.19,20) For example, when two
phases are in a solution, the less stable phase begins to
dissolve and the more stable phase grows until the less stable
phase has dissolved completely.5,6)
In this study, we demonstrate that SMPT is eective for the
production of a metastable phase using acetaminophen. The
SMPT of acetaminophen into the metastable phase form II
was induced by the following procedure. First, crystals of
trihydrate, which is less stable than form II, were obtained by
using a polymer templating technique (the details will be
described later). Second, form II seed crystals were prepared
by ultrasonic irradiation as described in a previous paper.18)
Third, SMPT was triggered by the addition of form II seed
crystals to the saturated solution including trihydrate crystals.
The route to obtain acetaminophen form II crystals is
summarized in Fig. 1. In addition, we investigated whether
this method is applicable to large-scale conditions.
Acetaminophen with a purity of 98% was purchased from
Acros and recrystallized before use. This material was conrmed to be form I by powder X-ray diraction (PXRD).
Ultrapure water (18.2 M cm, Komatsu Electronics UL Pure)
was used as the solvent in all experiments. An adhesive
(Cemedine Super XG No. 777), which is based on an acrylicmodied silicone polymer, was used as the polymer to induce

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Appl. Phys. Express 10, 015501 (2017)

Y. Mori et al.

crystallization. The adhesive was cured in air at room

temperature and then cut into disks (about 1.5 mm thick and
8 mm in diameter) for the crystallization experiments.
Aqueous acetaminophen solution (24, 32, and 40 mg=ml)
was prepared by dissolving acetaminophen in ultrapure water
in a Teon vessel. The solution was heated at 70 C for 3 h in
a drying oven (As One DO-450A). After ltration (0.2 m),
0.8 ml aliquots were dispensed into 1 ml glass vials placed
in a block incubator at 70 C. The shaped polymer was
previously added to glass vials prior to dispensing (eight
samples). For comparison, we also prepared samples without
the addition of the polymer (four samples). These samples
were placed in an incubator at 55 C and then cooled to 0 C
(supersaturation I = 2.5, 3.7, and 4.8) at a constant rate of
3 C=h. After the constant cooling, they were maintained
at that temperature for about one month. We investigated
the crystallization probability obtained one month after the
solution temperature reached 0 C. The crystallization probability was calculated as (ncry=ntotal ) 100, where ncry and
ntotal are the number of crystallized samples and the number
of total samples, respectively. The supersaturations of forms I
and II were calculated using the formula = (C Ce)=Ce,
where C is the acetaminophen concentration and Ce is the
solubility of acetaminophen forms I and II. Ce was calculated
by using the values obtained from a previous paper.18) The
shape of the obtained crystals was observed under an inverted
microscope (Nikon Eclipse TS 100). The polymorphs were
identied by single-crystal X-ray diraction (Rigaku R-AXIS
RAPID) or powder X-ray diraction (Rigaku SmartLab).
The crystallization probability obtained one month after
the solution temperature reached 0 C and photographs of the
obtained crystals are shown in Fig. 2. Without the addition of
the polymer, no spontaneous crystallization occurred at any
concentration for one month. On the other hand, when the
polymer was added, a large crystal or many small crystals
(thin platelike crystals) were obtained. Among the crystals
obtained by this method, the large crystal was subjected to
structural determination by single-crystal X-ray diraction.
The crystal was found to be trihydrate [C8H15NO5, orthorhombic, space group Pbca, a = 7.3215(2), b = 12.6028(3),
c = 22.6396(5) , and V = 2088.98(8) 3]. Although the
structural analysis of the small crystals was not performed,
we considered that the small crystals were also trihydrate for
the following reasons. The solubility of the small crystals was
higher than those of forms I and II in the temperature range of
1030 C, as will be described later. Therefore, the crystals
were not form I or II. As for form III, which is the most
unstable phase among the three anhydrous polymorphs, it has
been reported that the SMPT of form III into form I occurred
in about 7 s.6) In this study, we did not observe SMPT from
small crystals into form I for at least 7 d in the temperature
range of 030 C. Thus, the crystals were certainly not
form III. For the above reasons, we concluded that the small
crystals were trihydrate, just like the large crystal. In the case
of a low concentration of acetaminophen (24 mg=ml), a large
trihydrate crystal was obtained with high probability. Such a
large trihydrate crystal with dimensions up to about 4.5
3.9 0.68 mm3 has not been reported so far. When the
solution contained a high concentration of acetaminophen
(40 mg=ml), many small trihydrate crystals were obtained
with high probability. The nucleation and growth of

Fig. 2. Crystallization probability of acetaminophen trihydrate with and

without addition of polymer at acetaminophen concentrations of 24, 32, and
40 mg=ml. Photographs of trihydrate obtained by the polymer templating
technique are shown below.

Fig. 3. In situ observation of nucleation and growth of trihydrate.

The initiation of nucleation was dened as 0 min. A stick-shaped polymer
[white body in (a)] was immersed in aqueous acetaminophen solution.

trihydrate was observed in situ, as shown in Fig. 3. This

result demonstrated that trihydrate crystals were nucleated
from the surface of the polymer.
We investigated the stability of the trihydrate crystals
in solution. It has been reported that trihydrate is physically
stable in ice-cold aqueous suspension, but transforms into
form I via SMPT at temperatures above 5 C.14) On the other
hand, the trihydrate crystals obtained in this study did not
transform into form I or II for 7 d, although the samples
with solution were placed in a constant-temperature water
bath at 20 or 30 C. The crystals partially dissolved with
increasing temperature, but they remained in their trihydrate
form. These results demonstrated that the trihydrate crystals
in solution had a higher stability than those in the previously
reported study.
The reasons for the stability of the trihydrate crystals in
solution were as follows. The trihydrate crystals nucleated
from the surface of the polymer as shown in Fig. 3. Recently,
a polymer templating technique (polymer-induced heteronucleation) has been established as an eective method
of selecting and discovering polymorphs in various compounds.2124) The functional group on the polymer surface
plays an important role in phase selection.2527) Therefore, it
is probable that the functional group on the polymer surface
used in this study acts advantageously on the selective crystallization of trihydrate. The trihydrate crystals in this study
were stable in solution because they were crystallized with
100% purity by the polymer templating technique, and then

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Appl. Phys. Express 10, 015501 (2017)

Y. Mori et al.

Fig. 4. Solubilitytemperature diagram and tting curves for form I,

form II, and trihydrate of acetaminophen in water.

the supersaturation of the solution was lowered within the

metastable zone of form I after trihydrate crystallization. If
no form I crystals are simultaneously obtained by a polymer
templating technique and form I crystals do not newly
nucleate in solution, SMPT into form I will not occur. Note
that form I and trihydrate crystals coexisted in solution at
0 C for a long time (at least 4 d) owing to the slight
dierence in solubility. When the solution temperature was
increased to 10 C, SMPT into form I was accelerated and
completed in a day because the dierence in solubility
increased with increasing temperature. Therefore, whether or
not the purity of the trihydrate crystals is 100% can be easily
determined by keeping the sample at temperatures above
10 C for a day. From these results, we conclude that 100%
purity is a key factor for obtaining a less stable phase.
We measured the solubility of trihydrate in water using the
trihydrate crystals obtained in this study. The measurement
temperatures were 10, 20, and 30 C. The detailed method
of determining the solubility of trihydrate is the same as
described in our previous report. Figure 4 shows the measured solubility data for trihydrate at 10, 20, and 30 C. For
comparison, Fig. 4 also includes solubility data for forms I
and II, which were measured previously by our group.18)
These data were tted with an exponential curve. From these
results, we found that the solubilities of form I, form II,
and trihydrate in water in the range of 1030 C were in
the following order: form I < form II < trihydrate. In addition, with increasing temperature, the dierence in solubility
between trihydrate and form I or II increased.
Finally, we decided to conduct SMPT, because we
succeeded in crystallizing stable trihydrate and found that
the solubility of trihydrate was higher than that of form II
crystals. An aqueous acetaminophen solution (44 mg=ml)
was prepared and trihydrate crystals were obtained at 0 C by
using a polymer templating technique as described previously
(volume of saturated solution including trihydrate crystals:
1.7 ml). The driving force of SMPT is the dierence in
solubility between the phases. The dierence in solubility
between form II and trihydrate at 0 C is too small to promote
SMPT. Therefore, SMPT was performed at 20 C. Form II
seed crystals were prepared by ultrasonic irradiation,18) and
the solution including form II crystals was added to the
saturated solution including trihydrate crystals with a pipette.

Fig. 5. (a)(d) Growth process of acetaminophen form II via SMPT from

trihydrate into form II. (e) PXRD pattern of the obtained crystals via SMPT.

SMPT was triggered by the addition of droplets (volume of

solution: about 2080 l; number of form II crystals included
in solution: about 1050). We observed the growth process
of form II via SMPT under a microscope. Figures 5(a)5(d)
show the growth process of form II via SMPT after the
addition of form II seed crystals. The form II seed crystals
gradually grew at the expense of the dissolving trihydrate
crystals, and nally all the trihydrate crystals in solution were
transformed into form II crystals in about 4 h. The PXRD
pattern of the obtained crystals via SMPT is shown in
Fig. 5(e), and it matches well with that of form II.5) After
SMPT from trihydrate into form II was complete, the
obtained form II crystals were kept in solution for at least
2 d. As a result, we conrmed that SMPT into form I did not
occur. These results indicate that the saturated solution
including trihydrate crystals and the droplet added in order to
trigger SMPT did not include form I.
The stability of form II obtained via SMPT (ve samples)
was assessed by PXRD. For comparison, we also assessed
the stability of form II obtained by ultrasonic irradiation
(seven samples). In this study, the stability assessment of
form II was performed in severe environments in order to
accelerate the phase transformation, because it was found that
the form II grown by our group was stable for a long time
(at least 11 months) in air at room temperature.18) Form II
crystals obtained by each method were ground in a mortar
and then the powdered form II was stored under hightemperature and high-humidity conditions (HH conditions:
40 2 C, 80 5% RH). PXRD was recorded periodically
until form II was transformed into form I. Forms I and II
have characteristic peaks at around 26.5 and 24, respectively. The peak intensity ratio [PII=(PI + PII)] was calculated
as an indicator for assessing the stability of form II. PI is the
peak intensity at around 26.5 and PII is the peak intensity at
around 24. Figure 6 shows the stability of form II obtained

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Appl. Phys. Express 10, 015501 (2017)

Y. Mori et al.

solution and did not undergo SMPT into form I. On the

basis of these results, we succeeded in obtaining form II
via SMPT from trihydrate into form II. The stability of
form II obtained via SMPT was equal to or higher than that
of form II obtained by ultrasonic irradiation. In addition, this
method was applicable to large-scale conditions. Therefore,
we conclude that SMPT is eective for the production of
the metastable phase of acetaminophen.

Fig. 6. Stability of form II obtained by ultrasonic irradiation and via

SMPT under high-temperature and high-humidity conditions.

by dierent growth methods: ultrasonic irradiation and

SMPT. A high peak intensity ratio means that the sample
remains in form II, whereas a low ratio means that the sample
undergoes phase transformation into form I. These results
indicate that the stability of form II obtained via SMPT was
equal to or higher than that obtained by ultrasonic irradiation.
The reasons why the stability of form II depended on the
growth method used (ultrasonic irradiation or SMPT) were
as follows. The stability of form II correlates with its crystal
quality. It has been reported that crystal defects such as
inclusions of mother liquor in the crystal induce the phase
transformation of form II into form I during storage.28) In
general, these inclusions tend to be formed at high growth
rates.29,30) In the case of ultrasonic irradiation, all form II
crystals nucleated and grew at once from a highly supersaturated solution (II = 3.3). In the case of SMPT, although
form II crystallized by ultrasonic irradiation was used for
the seed crystals, form II gradually grew from low supersaturation (II = 0.7), which is a saturated concentration of
trihydrate at 20 C. Presumably, the lower growth rate that
resulted from low supersaturation reduced the number of
inclusions of the mother liquor formed in a form II crystal,
and thus the stability of form II was improved.
Finally, we investigated whether SMPT from trihydrate
into form II would be applicable to large-scale conditions
(volume of saturated solution including trihydrate crystals:
15 ml). The results of this experiment conrmed that form II
can be obtained via SMPT under large-scale conditions.
Thus, we conclude that SMPT from trihydrate into form II
will be used as a new method of obtaining the metastable
phase form II of acetaminophen. From these results, we
conclude that SMPT is eective for the production of the
metastable phase of pharmaceutical compounds.
In this study, we aimed to develop a technology for
obtaining the metastable phase form II of acetaminophen.
The key results are as follows. We succeeded in crystallizing
trihydrate by using a polymer templating technique. The
trihydrate crystals obtained in this study were stable in

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