Different Solid Forms of Vitamin K3and Their Effect on the Chemical Stability

Article abstract of DOI:10.1021/acs.cgd.0c01324

MSB, the commercially available form of vitamin K3, has been widely applied in medicine, the nutrition industry, and livestock feed for decades. However, undesired degradation in an alkaline environment significantly decreases its efficacy and limits its application. Herein, polymorphism screening was performed on MSB to obtain solid forms with improved chemical stability. Two new solid forms were discovered, including form A and HB. Their crystal structures were elucidated by single crystal X-ray diffraction, and these forms were adequately characterized by powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, and dynamic vapor sorption. The transformation relationships between these solid forms were fully discussed. Single-crystal-to-single-crystal transformation behavior was also detected by X-ray diffraction and hot-stage microscopy. The chemical stability in an alkaline environment of the newly discovered forms was investigated and compared with that of the marketed form. It was found that form A significantly alleviates the degradation of MSB. This gratifying chemical stability may be attributed to its compact packing pattern and the molecular conformation advantage.

Full text of DOI:10.1021/acs.cgd.0c01324

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Article
Different Solid Forms of Vitamin K3 and Their Effect on the Chemical
Stability
Zeen Yang, Bingqing Zhu, Yuhang Jiang, Zaiyong Zhang, Wenjuan Dai, and Xuefeng Mei*
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ABSTRACT: MSB, the commercially available form of vitamin K3,
has been widely applied in medicine, the nutrition industry, and
livestock feed for decades. However, undesired degradation in an
alkaline environment significantly decreases its efficacy and limits its
application. Herein, polymorphism screening was performed on
MSB to obtain solid forms with improved chemical stability. Two
new solid forms were discovered, including form A and HB. Their
crystal structures were elucidated by single crystal X-ray diffraction,
and these forms were adequately characterized by powder X-ray
diffraction, differential scanning calorimetry, thermogravimetric analysis, and dynamic vapor sorption. The transformation
relationships between these solid forms were fully discussed. Single-crystal-to-single-crystal transformation behavior was also
detected by X-ray diffraction and hot-stage microscopy. The chemical stability in an alkaline environment of the newly discovered
forms was investigated and compared with that of the marketed form. It was found that form A significantly alleviates the
degradation of MSB. This gratifying chemical stability may be attributed to its compact packing pattern and the molecular
conformation advantage.
Scheme 1. Chemical Structure of MSB
INTRODUCTION
■
Active pharmaceutical ingredients (APIs) may exist in a variety
of solid forms, such as amorphous forms, polymorphs,
hydrates, and solvates.1 Their different molecular conforma-
tions and crystal packing can result in different physicochem-
ical properties, such as stability, flowability, tableting, perform-
ance, solubility, and dissolution rate, which are of vital
importance in the pharmaceutical industry.2−7 Therefore, it
is crucial to understand the existence of each form of APIs and
their specific crystallization conditions, not only for choosing
the optimal form but also to prevent accidental transformation
during the manufacture processes, which may lead to
potentially harmful results.8−10
Vitamin K is an essential substance for the synthesis of
coagulation factors VII, IX, and X to maintain blood
coagulation.11−13 Vitamin K deficiency can lead to prolonged
clotting time, subcutaneous hemorrhage and hematuria, or
even death in severe cases.14−17 Recent studies have found that
vitamin K is also involved in bone metabolism and vascular
calcifications.18−20 Vitamin K3 (VK3), as a synthetic vitamin K,
can be produced in large-scale and has been widely used in
medicine, the nutrition industry, and livestock feed.12,14,21
Menadione sodium bisulfite (MSB, Scheme 1) is the
commercially available form of VK3. Its annual usage is nearly
7000 t, and the demand is still growing rapidly. However, MSB
is highly sensitive to an alkaline environment.22,23 It was
reported that MSB was the least stable vitamin in feed
additives due to the presence of minerals and large amounts of
alkaline substances such as sodium carbonate, sodium
bicarbonate, and choline chloride.24,25 The severe degradation
is detrimental to the efficacy of MSB. To ensure an adequate
intake of VK3, an excessive amount of MSB has to be added in
nutritional supplements or feed additives.22,26 To our best
knowledge, no practical solution has been proposed to improve
its chemical stability. Therefore, inhibiting degradation in an
alkaline environment is crucial for the application of MSB.
Although MSB has been widely used for decades, there have
been few studies concerning its solid form landscape. There
was only a crystal structure of dihydrate (HA, CSD refcode:
NAMOTS) reported, which is the currently commercial solid
Received: September 24, 2020
Revised: December 7, 2020
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Thermogravimetric Analysis (TGA). A TGA-55 equipment (TA
Instruments) was used for TGA with sample masses of approximately
5 mg. These analyses were performed to test and quantify any solvents
contained in the crystal forms. For all experiments, the powder
samples were placed in open aluminum oxide pans with the heating
rate of 10 °C/min, and dry nitrogen was employed as the purge gas at
40 mL/min.
Differential Scanning Calorimetry (DSC). DSC experiments
were conducted on a DSC 8500 instrument (PerkinElmer), and the
flow rate of dry nitrogen was 50 mL/min. The samples weighing 3−5
mg were placed and heated in hermetically sealed aluminum pans. For
all DSC experiments, the materials were heated from 30 °C to the
suitable temperature with a heating rate of 10 °C/min.
Dynamic Vapor Sorption (DVS). An Intrinsic DVS instrument
(Surface Measurement Systems, Ltd.) was used to measure the
process of water sorption and desorption. The powder samples were
placed on the balance, and the water sorption was measured over a
relative humidity (RH) range of 0−95%, and then decreased to 0%
RH for desorption at 25 °C. The next RH step with an interval of 5%
was performed if the mass change was less than 0.02% within 10 min.
Hot-Stage Microscopy (HSM). HSM experiments were carried
out on an SZ61TR polarizing microscope (Olympus) and an XPH-
300 hot stage equipped with a JVC TK-C9201 EC digital video
recorder from Shanghai Changfang Optical Instrument Co., Ltd.
HSM experiments were performed to figure out the transformations
of various forms during heating of the samples.
Chemical Stability Study. To avoid the effect of particle size on
the results, all forms of MSB were ground and sieved through the 100-
mesh sieves. The obtained powders with a uniform particle size were
used for the chemical stability test. Accurately weighed powders of 5
mg of MSB and 5 of mg sodium carbonate (n = 3) were evenly mixed
and placed at 25 °C and 45% RH. The resulting powders were
extracted with methanol and submitted to HPLC analysis after storing
at the intervals of 5, 10, 15, and 20 days. The sample concentrations
of MSB were determined by an Agilent 1260 series HPLC from
Agilent Technologies Co., Ltd., equipped with a quaternary pump
(G1311C), diode-array detector (G1315D) set to 230 nm, and a 4.6
× 50 mm, 1.8 μm Agilent Eclipse plus C18 column. The mobile phase
consisting of 5 mmol/L tetrabutylammonium bromide aqueous
solution (eluent A) and methanol (eluent B) was run at 1.0 mL/
min. The column temperature was set to 30 °C, and the injection
volume was 20 μL. The gradient elution procedure started at 70% A
and held for 2 min, and then linearly decreased to 10% A over 10 min
and held for 2 min, and finally returned to the initial composition and
held for 3 min.
form. However, no solid-state characterization or physico-
chemical properties of this hydrate were reported. Thus, it is
necessary to identify and comprehensively characterize the
various solid forms of MSB to select a superior form with great
chemical stability in formulation development.
The work presented here focuses on the effect of different
solid forms of MSB on its chemical stability. We disclose two
novel solid forms of MSB, including a new anhydrous form A
and a new 2.5 hydrate form (HB). Single crystal X-ray
diffraction (SCXRD) was conducted to elucidate the crystal
structures of these forms, and the physicochemical properties
of all solid forms were comprehensively investigated by powder
X-ray diffraction (PXRD), hot-stage microscopy (HSM),
thermal analysis (TGA and DSC), and dynamic vapor sorption
(DVS) isotherms. Moreover, the chemical stability of the
newly discovered forms (form A and HB) was evaluated and
compared with that of the marketed form (HA). Furthermore,
the underlying mechanism affecting MSB’s chemical stability
under various solid forms was discussed.
EXPERIMENTAL SECTION
■
Materials. The sample of MSB with a purity greater than 98%
used in this work was purchased from Shanghai Aladdin Bio-Chem
Technology Co., Ltd. (Shanghai, China). The untreated sample was
proved by PXRD to be a single phase (HA). All analytical grade
solvents in the present study were purchased from Sinopharm
Chemical Reagent Co., Ltd., and were used without further
purification.
Preparation of Form A. 10 mg of MSB was dissolved in 2 mL of
ethanol. The resulting solution was filtered through a 0.45 μm nylon
filter and placed at 50 °C for evaporation. After a few days, colorless
block crystals were harvested and submitted to X-ray diffraction
analysis.
Preparation of HA. 10 mg of MSB was dissolved in 2 mL of
acetone. The resulting solution was filtered through a 0.45 μm nylon
filter into a clean vial and placed at room temperature for evaporation.
After a few days, transparent rod-like crystal was obtained and
confirmed as HA, which is a dihydrate.
Preparation of HB. 20 mg of MSB was dissolved in 0.5 mL of a
1:1 (v/v) mixture of isopropanol and water. The resulting solution
was filtered through a 0.45 μm nylon filter into a 4 mL glass vial,
which was then placed in a large glass vial containing 5 mL of
isopropanol and sealed. After a week, thin sheet-like crystals were
obtained for crystal structure identification. The structure shows that
HB is a 2.5 hydrate.
Powder X-ray Diffraction (PXRD). PXRD patterns in this study
were obtained at constant or variable-temperature on a D8 Advance
(Bruker) X-ray diffractometer using Cu Kα radiation, with the voltage
and current of the generator being set to 40 kV and 40 mA,
respectively. The standard scanning range was 3−40° 2θ with a scan
rate of 0.1 s/step at ambient temperature. The collected data were
imaged and integrated with RINT Rapid, and peak analysis was
performed using MDI Jade software.
Single Crystal X-ray Diffraction (SCXRD). X-ray diffraction
collections of all single crystals of MSB were conducted on an APEX
II CCD diffractometer (Bruker) with Mo Kα radiation (λ = 0.71073
Å). Suitable crystals were mounted on loops, and the diffraction was
carried out at 170(0) K. The program SAINT was used for integrating
and scaling of intensity data, and the absorption effect of the data was
corrected using SADABS. The crystal structures were solved by the
direct methods on SHELXTL and subsequently refined by full-matrix
least-squares with SHELXL-2017 software. All non-hydrogen atoms
were refined with isotropic atomic displacement parameters, and all
hydrogen atoms were located in calculated positions and refined with
the riding model. Crystallographic data in cif format have been
deposited in the Cambridge Crystallographic Data Center, CCDC
Nos. 2032468−2032470 for form A, HA, and HB, respectively.
RESULTS AND DISCUSSION
■
Preparation of Various Forms. In order to obtain as
many new solid forms as possible, different crystallization
methods were conducted in this study. Three solid forms,
anhydrous form A and two hydrates (HA and HB), were
obtained from the crystallization screening. Selected results of
crystallization experiments are listed in Table S1. Form A was
routinely obtained at room temperature in the slurry
experiments with organic solvents, but when the solvent
contains water, HA or HB can be obtained. Water activity
plays a crucial role in controlling the formation of different
hydrates. When the water content is low, such as 5% in acetone
or acetonitrile, HA is obtained. However, when the water
content rises, for instance, 10% in acetone or 15% in
acetonitrile, HB will be acquired (Table S1). In addition,
HA can be obtained by evaporating in some moderate polar
solvents at room temperature. However, at higher temperature,
the resulting powder was found to be form A. The solubility in
water of the three solid forms has been tested. The result
shows that the solubility in water of all three forms is greater
than 20 mg/mL. PXRD patterns of the three solid forms are
B
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Figure 1. Polarizing microscopy pictures of form A, HA, and HB.
shown in Figure 2. All the peaks generated in the measured
patterns of the obtained powders show a close match with the
crystal of form A was obtained by evaporation from an ethanol
solution at 50 °C. The structure was determined in monoclinic
space group P21/c with one molecule of MSB in the
asymmetric unit. As shown in Figure 3, each MSB molecule
interacts with three Na+ cations, giving rise to pipelines of the
interconnected Na+ octahedral structure. A single crystal of
HA, which contains 2 equiv of water, was obtained through
slow evaporation at room temperature, and HB containing 2.5
equiv of water was obtained by anti-solvent crystallization. In
HA, each MSB molecule coordinates with two Na+ cations,
and two adjacent Na+ cations are connected by two molecules
of water. In HB, although HB appears to have a pipe-like
structure, the packing pattern is more complicated. There are
isolated MSB molecules which are not involved in coordina-
tion with Na+ cations (highlighted in green circles in Figure
3b). Moreover, two types of water molecules exist in HB: one
is connected between two adjacent Na+ cations, which is the
same as that of HA, and the other forms a single coordination
with only one Na+ cation (highlighted in blue circles in Figure
3b). Thus, the structure of HA has higher symmetry than HB.
As shown in Figure 4, the Na+ cations in all three forms are
found to be on the center of the octahedron coordinated by
oxygen atoms. For form A, the Na+ cation forms an octahedral
coordination with six oxygen atoms of four MSB molecules,
while the Na+ cation of HA forms an octahedron with two
MSB molecules and four water molecules. As for HB, although
the Na+ cations are also arranged in the octahedron, there are
Figure 2. PXRD patterns of various solid forms of MSB.
simulated patterns acquired from the single crystal diffraction
data, indicating the formation of the highly pure phases. The
polarizing microscopy pictures of the three forms are illustrated
in Figure 1. Form A crystallizes as rhombus. HA presents a
rod-like morphology, whereas HB shows a thin sheet-like
shape.
Single Crystal Structure Analysis. Crystallographic data
and refinement details are given in Table 1. The rhombic
Table 1. Crystallographic Data and Structure Refinement Parameters for Various Forms of MSB
form A
HA
HB
formula
crystal system
space group
temp (K)
a (Å)
C11H9O5SNa
monoclinic
P21/c
C11H9O5SNa·2H2O
monoclinic
P21/c
4C11H9O5SNa·10H2O
triclinic
P1
̅
170(0)
170(0)
170(0)
16.1101(12)
5.5518(4)
11.7768(8)
90
90.100(17)
90
1053.32(13)
1.742
4
15.9198(4)
5.8862(1)
14.9833(4)
90
115.467(1)
90
1267.61(5)
1.636
4
11.4974(5)
15.6108(7)
15.7279(7)
94.8460(10)
90.148(2)
100.272(2)
2767.28(2)
1.542
b (Å)
c (Å)
α (deg)
β (deg)
γ (deg)
V (Å3)
ρCal (g/cm3)
Z
8
λ (Mo Kα)
S
Rint
0.71073
1.064
0.0633
0.71073
1.071
0.0272
0.71073
1.047
a
0
R1 [I > 2σ(I)]
wR2
0.0399
0.0941
0.0382
0.0913
0.0407
0.1096
a
The crystal of HB is a twin crystal.
C
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Figure 3. (a) The pipe-like structures of MSB solid modifications. (b) 2-D crystal packing of MSB solid modifications. For a clearer observation,
the hydrogen atoms in the structures are omitted and the oxygen atoms of water are presented as spheres, and the rest of figures are also the same.
Figure 4. Octahedral coordination structures of Na+ cation of (a) form A, (b) HA, and (c) HB.
Figure 5. Superposed TGA (red lines) and DSC (blue lines) analyses for (a) form A, (b) HA, and (c) HB.
two kinds of Na+ cations: one coordinated with four water
molecules and the other coordinated with five water molecules.
Thermal Analysis. Thermal analyses were performed on
these various forms of MSB to evaluate their physicochemical
properties. Superposed TGA and DSC analyses of these three
forms are shown in Figure 5. There is no mass loss before the
decomposition temperature in form A, and it has only one
endothermic peak at about 155 °C, corresponding to its
decomposition temperature in the DSC curve. Comparatively,
an obvious endothermic peak prior to decomposition of HA,
which is related to the dehydration process at approximately
110 °C, can be observed in the DSC curve. The TGA plot of
HA shows 11.3% experimental weight loss at the same
temperature, in agreement with the theoretical value of 11.5%.
Notably, HB presents two different endothermic peaks at
about 50 and 110 °C before decomposition, indicating that the
dehydration process of HB is divided into two stages. In the
TGA plot, the mass loss of HB is measured to be 3.2% in the
first stage at about 55 °C, corresponding to 0.5 equiv of water
(calculated value: 2.8%). As the temperature further ramping
up, the TGA plot shows 10.6% mass loss at about 110 °C,
corresponding to 2 equiv of water (calculated value: 11.2%).
The two-stage dehydration process is due to the existence of
two types of water molecules in HB, which has been disclosed
in its single crystal structure (Figure 3).
The phase transformation from HB to HA was further
verified by VT-XRPD, and the result is shown in Figure S1. It
is obvious that the position of the peaks of HB remains intact
in the temperature range from room temperature to 50 °C. At
60 °C, additional peaks at 2θ = 6.2°, 12.2°, and 24.6° arise,
which are the characteristic peaks of HA, suggesting that the
phase transformation was in progress. As the sample was
further heated, characteristic peaks of HB at 2θ = 5.5°, 11.5°,
29.0°, and 35.0° were gradually weakened, whereas the new
peaks of HA were strengthened. At 90 °C, the characteristic
peaks of HB have disappeared, confirming that the conversion
to HA was completed.
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Single-Crystal-to-Single-Crystal (SCTSC) Transforma-
tion. The thermal results clearly suggest the transformation
pathway of HB and HA. On the basis of these results, a
SCTSC transformation experiment was devised and performed
by hot-stage microscopy and SCXRD. Crystals of HB were
heated on the hot-stage microscopy at 5 °C/min. An explicit
change in crystal surface morphology appeared at about 80 °C
(Figure S2). The crystal was re-examined by SCXRD after
being kept at 90 °C for 15 min. Although the single crystal was
slightly opaque, it retained mechanical integrity rather than
disintegrated into fine powders. The resulting single crystal
could be indexed to the unit cell of HA. The cell parameters of
the single crystal before and after heating are listed in Table S2.
The crystal structure shows that 0.5 equiv of water molecules
in HB are monocoordinated with Na+ cations. This partial
water molecules can be easily removed from the crystal by
heating, which is consistent with the result of TGA of HB. The
packing mode of the remaining 2 equiv of water molecules in
HB is the same as that of HA, which are connected between
two adjacent Na+ cations. The great resemblance in the crystal
packing of HA and HB allows the molecular movement during
single-crystal-to-single-crystal transformation.
Interconversion between Different Forms of MSB.
The thermal analysis reveals that HB will dehydrate and
transform to HA when heated. The two hydrates can also be
interconverted under different humidity. The DVS results of
form A and HA are shown in Figure S3. The powder of HA
was subjected to a 0-95-0% RH cycle. The result shows a
negligible moisture uptake prior to 75% RH. However, as the
RH is risen to 85%, the mass of absorbed water alleviates and is
measured to be about 3.0%, which is close to 0.5 equiv of
water. This indicates that HA will be converted to HB above
80% RH. The phase of HB is maintained until the RH is
decreased to about 30% during desorption, and then converted
to HA. Notably, HA no longer dehydrates upon subsequently
decreasing RH to 0%. The DVS diagram of form A also reveals
stoichiometric hydration and dehydration patterns. A new
stage of water uptake appears at approximately 60% RH. The
mass of absorbed water (12.7%) is equal to 2 equiv of water,
demonstrating that form A has been converted to HA. When
the RH is risen to 80%, the increase of the mass reaches a
plateau and is measured to be about 3.1%, which is close to 0.5
equiv of water, indicating that the sample was converted to
HB. The DVS results explicitly denote the interconversion
between different solid forms of MSB, and the resulting
materials under different RH were confirmed by PXRD (Figure
S4). Characteristic peaks of HB were observed in PXRD after 4
h storage under the environment of 25 °C/80% RH (Figure
S5). Additionally, slurry experiments were conducted by
suspending HB in 2 mL of organic solvents and stirring for
24 h in a sealed glass vial. The results show that HB was
converted into form A in organic solvents (Table S3 and
Figure S6). Therefore, the interconversion relationship of
different solid forms of MSB is shown in Scheme 2.
Scheme 2. Transformation Relationship of MSB Solid-State
Forms
storage. However, there was essentially no color change
detected in form A. The remaining content of MSB in all three
forms over time was determined by HPLC, and the results are
shown in Figure 6b. The marketed form (HA) was quickly
degraded to 82% after 5 days of storage, which was consistent
with the previous reports.22,23 A rapid drop in the content was
also found in HB, and there was almost no MSB left after 20
days of storage under stressed condition. To our surprise, a
significantly slower degradation rate (96.4%, 90.9%, 88.5%, and
85.6% after 5, 10, 15, and 20 days, respectively) was observed
in form A.
The reasons for such a significant difference in chemical
stability were then explored. Packing coefficient is usually used
to reflect the compactness of crystal packing.27 The increase of
packing coefficient means that the crystals pack more
tightly.28−30 The packing coefficients of the three forms of
MSB are listed in Table 2. According to the results, form A
packs the most tightly and HB packs the least tightly. Garcia-
Garibay et al. reported that decreased packing coefficient of the
lattice will facilitate rotational dynamics of the molecules in
crystal,31,32 which indicates the correlation between the rate of
molecular movement and the packing coefficients.33 Therefore,
we suppose that compact crystal packing of form A hinders the
molecular movement and thus lowers its collision probability
with alkali, so form A is more resistant to the degradation.
The difference of chemical stability between the three forms
of MSB can also be explained from the perspective of
degradation mechanism. MSB undergoes β-elimination in the
existence of alkali.34−36 As shown in Scheme 3, as the proton is
removed, the bisulfite leaving group departs and simulta-
neously forms a double bond.37,38 The degradation product of
all three forms was confirmed by HPLC (Figure S7). The
retention time of MSB is 6.05 min, and the main degradation
impurity was detected at 7.35 min, which corresponds to β-
elimination product, menadione (MN). Since β-elimination of
MSB occurs most often in an anti-planar arrangement of the
C8−H bond and C9−S bond (highlighted in red in Scheme
3), the conformation of the MSB molecule, especially the
dihedral angle of H−C8−C9−S, has a great effect on the rate
of the degradation reaction. The overlay diagram of molecules
is presented in Figure 7, and the values of the dihedral angle
between H−C8−C9−S in all solid forms are listed in Table 3.
It can be seen that HA and HB have similar dihedral angles
which were close to 180°. In contrast, the dihedral angle of
form A differs greatly from that of HA and HB, which is
Stability in Alkaline Environment. MSB is easily
subjected to elimination in an alkaline environment. The
presence of minerals and large amounts of alkaline substances
in the feed is detrimental to the stability of MSB. In this study,
the chemical stability studies were performed for all forms of
MSB by mixing with sodium carbonate, which is routinely
added to supplements and feeds as a leavening agent and
acidity regulator. As shown in Figure 6a, the appearance of HA
and HB samples were found to turn brown after 20 days of
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Figure 6. (a) Photographs of form A, HA, and HB mixed with sodium carbonate after 20 days of storage under 25 °C/45% RH conditions in
comparison with raw material at 0 days. (b) The remaining content of MSB in various solid forms after stressed under an alkaline environment.
Table 2. Value of Packing Coefficients of Form A, HA, and
HB
solid forms
packing coefficient
form A
HA
HB
0.82
0.74
0.70
determined to be about 156°. For the MSB molecule, when the
dihedral angle between H−C8−C9−S is far from 180°, more
energy is required to align them into an ideal geometry for β-
elimination, especially in the solid state. Thus, form A is more
resistant to degradation compared with HA and HB.
In summary, for the investigated three forms (form A, HA,
and HB), form A was observed to be significantly more stable
than HA and HB because of the compact crystal packing and
its less ideal conformation for β-elimination. As for HA and
HB, although HA and HB have a similar dihedral angle
between H−C8−C9−S, HA has a more compact packing
pattern and higher symmetry than HB. Therefore, the order of
chemical stability is form A > HA > HB.
Figure 7. (a) Overlay of Newman projection along C8−C9 bond of
form A (red), HA and HB (green). (b) Overlay of unique molecules
in crystal structures of form A (red), HA (gold), and HB (green).
Table 3. Values of Dihedral Angle of Reactive Sites of Form
A, HA, and HB
solid forms
dihedral angle between H−C8−C9−S (deg)
form A
HA
156.14
170.17
HB
173.31, 172.70, 172.44, 168.96
CONCLUSIONS
change. Moreover, chemical stability of the newly discovered
forms was compared with the marketed form (HA). To our
surprise, form A shows superior chemical stability compared
with HA and HB in an alkaline environment. After a close look
at the crystal structures of the various forms of MSB, we
propose that the compact crystal packing and the smaller
dihedral angle of the β-elimination reaction site alleviate the
severe degradation of MSB. The newly discovered form A
should be a superior solid form in the application of vitamin K3
in terms of its improved stability.
■
In summary, a comprehensive polymorphic screening of MSB
resulted in the discovery of a new anhydrate (form A) and a
hydrate (HB). The crystal structures of these forms were
revealed in this work. The conditions for transformation
among these phases were revealed. Two hydrates were
converted into form A in most organic solvents, and form A
can be converted into HA or HB under different relative
humidity. Interestingly, SCTSC transformation was observed
from HB to HA when properly handled by a temperature
a
Scheme 3. β-Elimination of MSB Degradation
a
B means alkali.
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Notes
ASSOCIATED CONTENT
■
The authors declare no competing financial interest.
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.cgd.0c01324.
ACKNOWLEDGMENTS
■
This research work was financially supported by the Major
National Science and Technology (Grant No. 2017ZX091-
01001) and Natural Science Foundation of Shanghai (Grant
No. 18ZR1447900).
Summary of crystallization screening experiment, solid-
state transformation from HB to HA monitored by VT-
PXRD, hot-stage microscopy snapshots of the SCTSC
transformation from HB to HA, crystallography
parameters of the original HB single crystal and the
resulting HA single crystal through the SCTSC induced
by heating, DVS plots for forms A and HA, PXRD
diagrams of samples under different humidity conditions
after DVS, PXRD diagrams of starting sample of form A
and the sample after 4 h storage under the environment
of 25 °C/80% RH, summary of slurry experiments of
HB in different organic solvents, PXRD diagrams of
resulting powders obtained after 24 h slurry experiments
of HB in different organic solvents, and HPLC spectral
of three forms after 20 days of storage (PDF)
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Accession Codes
CCDC 2032468−2032470 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Xuefeng Mei − Pharmaceutical Analytical & Solid-State
Chemistry Research Center, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, Shanghai 201203,
China; University of Chinese Academy of Sciences, Beijing
100049, China; orcid.org/0000-0002-8945-5794;
Email: xuefengmei@simm.ac.cn
Authors
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Morris, J.; Henry, R.; Spanton, S.; Dziki, W.; Porter, W.; Quick, J.;
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Dev. 2000, 4, 413−417.
Zeen Yang − Pharmaceutical Analytical & Solid-State
Chemistry Research Center, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, Shanghai 201203,
China; University of Chinese Academy of Sciences, Beijing
100049, China
Bingqing Zhu − Pharmaceutical Analytical & Solid-State
Chemistry Research Center, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, Shanghai 201203,
China
Yuhang Jiang − Pharmaceutical Analytical & Solid-State
Chemistry Research Center, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, Shanghai 201203,
China; University of Chinese Academy of Sciences, Beijing
100049, China
Zaiyong Zhang − Pharmaceutical Analytical & Solid-State
Chemistry Research Center, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, Shanghai 201203,
China
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