Study on crystal morphology of penicillin sulfoxide in different solvents using binding energy

Article abstract of DOI:10.1021/op500362r

The binding energy of the solvent is an important factor in crystal morphology. In this study, binding energies of water, ethyl acetate, and butyl acetate on specific surfaces of penicillin sulfoxide were evaluated. Molecular modeling techniques based on the adsorption of solvent molecules on specific crystal surfaces were utilized to determine the binding energies. Our results show a strong association between the absolute value of the binding energy and crystallization. The results predicted by molecular modeling are well-fitted with experimental results. Efficient solvent selection and production process optimization were successfully achieved by using the methodology developed in this paper. Our study illustrates a novel strategy that can be used for the investigation of solvent effects.

Full text of DOI:10.1021/op500362r

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Full Paper
Study on Crystal Morphology of Penicillin Sulfoxide
in Different Solvents using Binding Energy
Dingding Jing, Ailing Liu, Jingkang Wang, and Huiming Xia
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/op500362r • Publication Date (Web): 09 Feb 2015
Downloaded from http://pubs.acs.org on February 18, 2015
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Study on Crystal Morphology of Penicillin Sulfoxide in Different
Solvents Using Binding Energy
1
1
2
3*
Dingding Jing , Ailing Liu , Jingkang Wang , Huiming Xia
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1
. Ringpu (Tianjin) Biology Pharmacy Company, Tianjin, P.R. China.
2. State Key Laboratory for Chemical Engineering and School of Chemical Engineering and
Technology, Tianjin University, Tianjin, P.R. China.
3. The Wilmer Eye Institute, Johns Hopkins University, School of Medicine, Baltimore, MD,
USA.
*Correspondence should be addressed to Dr. Huiming Xia. Address: The Wilmer Eye Institute,
Johns Hopkins University, School of Medicine, Baltimore, MD. Telephone:+86
02288958031.Fax:+86 02288958030. E-mail: jingydly@163.com.
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Table of Contents Graphic
There is a positive correlation between the absolute value of binding energy and
the affinity of adsorbate to the penicillin sulfoxide crystal face. Both ethyl acetate and
butyl acetate molecules hinder the adsorption process of penicillin sulfoxide on the
specific surfaces. As a result, the faces with higher binding energy have lower growth
rate and bigger surface area when the crystal grown from ethyl acetate and butyl
acetate. However, the opposite conclusion is obtained when the penicillin sulfoxide
crystal grown from water. The water molecules adsorbed on the faces could improve
the crystal growth by forming hydrogen bond with penicillin sulfoxide molecules.
Therefore, the faces of the penicillin sulfoxide crystal grown from water with higher
binding energy have higher growth rate and smaller surface area.
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A: ethyl acetate
B:butyl acetate
C: water
Bingding energy and area ratio of penicillin sulfoxide grown from different solvents.
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Abstract: Binding energy is an important factor by solvents on crystal morphology. In
this study, binding energy of water, ethyl acetate and butyl acetate molecule on
specific surfaces of penicillin sulfoxide are evaluated. Molecular modeling technique
based on the adsorption of solvent molecules on specific crystal surface was utilized
to determine the binding energy. Our results show a strong association between the
absolute value of the binding energy and crystallization. Predicted results by
molecular modeling are well fitted with experimental results. Efficient solvents
selection and production process optimization was successfully achieved by using the
methodology developed in this paper. Our study illustrated a novel strategy that can
be used for solvent effect investigation.
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Key words: Crystal morphology; Solvent effect; Surface docking, Binding energy;
Penicillin sulfoxide.
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1
. Introduction
Crystal morphology and size distribution will take great effect on the final
therapeutic behavior. Dissolution rate and bioavailability depend on the crystal size,
but also on the morphology. In different solvents, the relative growth rates of its
surfaces in different direction result in different morphology. The crystal morphology
could change from one-dimensional needle-like to three-dimensional block-like,
which may result in various changes including bulk density, dissolution rate and even
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bioavailability . Therefore, solvent effect on crystallization is always
comprehensively studied with priority. However, research on the solvent effect cannot
be carried out until a lot of solvent screening works are finished. The studies on the
solution crystal processes (include nucleation, growth and polymorphic
transformation) can be carried out efficiently by using on-line methods (such as
FBRM, PVM, IR, Raman and so on) except solvent screening studies. Considering so
many kinds of solvents, large amount of experimental works have to be done. As a
result, efficient methods for effective and expedite solvent selection are badly desired.
There have been two theories regarding the effect of solvent on crystallization.
One theory is that the interactions between solute and solvent on specific faces will
reduced the interfacial tension, which will further change crystallization profile. The
second theory is that preferential adsorption at the specific faces will inhibit crystal
growth as removal of bound additive poses an additional energy barrier for continued
growth.
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Based on the second theory, the prediction model of crystals induced by
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additives was developed and the binding energy examined to investigate the
interaction between crystal surfaces and additives. In this article, we use binding
energy concept to study the solvent effect on penicillin sulfoxide crystallization.
Penicillin
sulfoxide
(Fig.1)
is
acid
used
(7-ADCA)
to
by
produce
catalytic
7
-amido-3-methyl-3-cephem-4-carboxylic
14-18
ring-enlargement and enzymatic hydrolysis reaction
most important nucleuses of cephalosporin antibiotic.
and 7-ADCA is one of the
Figure 1. The chemical structure of penicillin sulfoxide
The crystal of penicillin sulfoxide grown from water displays a plate-like
morphology while the crystal grown from butyl acetate displays a bi-pyramidal
morphology. Different morphology of penicillin sulfoxide display different physical
and chemical properties including bulk density, crystal size, dissolution rate,
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bioavailability, hardness and appearance
. As a result, a detailed investigation on
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the solvent effect on penicillin sulfoxide is necessary.
By using Material Studio, the binding energy calculation and morphology
21,22
simulation were carried out with Attachment Energy (AE) model
to study the
association between morphology and the solvent effect. The simulation and
calculation results are compared with the crystal morphology of penicillin sulfoxide
obtained from experiments to further confirm the reliability of the methodology. Our
study exemplified a strategy of studying the solvent effect through binding energy on
crystal morphology. The methodology development in this study should benefit future
crystallization investigation.
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2
2
. Results and Discussion
.1 Crystal structure
The crystal structures of penicillin sulfoxide are determined by single crystal
X-Ray diffraction. The parameters of penicillin sulfoxide obtained from XRD and
structure minimization are listed in Table 1.
Table 1. The data of penicillin sulfoxide obtained from XRD and structure minimization.
XRD results
Structure minimization
C H N O S·1.5H O
Formula
C H N O S·1.5H O
1
6
18
2
5
2
16 18
2
5
2
crystal system
space groups
cell parameter (Å)
orthorhombic
orthorhombic
P2 2 2
P2 2 2
1 1 1
1
1
1
a = 8.413
b = 19.133
c = 23.116
α = 90.00°
ß = 90.00°
γ = 90.00°
3721
a = 7.936
b = 18.586
c = 22.542
α = 90.00°
ß = 90.00°
γ = 90.00°
3325
cell angle(°)
3
cell volume /Å
Z
8
8
3
calculated density /g/cm
1.335
1.494
Penicillin sulfoxide belongs to orthorhombic system. The space group is P2 2 2 ,
1
1 1
2
3
and there are 1.5 water molecules around one penicillin sulfoxide on average . After
the structure is determined by XRD, a simulation of crystal structure minimization are
carried out. The optimized structure is used to perform the crystal morphology
simulation and binding energy calculation.
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Figure 2. Two associated molecules of penicillin sulfoxide (left) and the molecular packing
arrangement of penicillin sulfoxide hydrate (right). OW1, OW2 and OW3 are the oxygen atoms of
water molecules.
Penicillin sulfoxide can form hydrogen bond with another molecule by
intermolecular bond, such as N1—H1---O8 (Fig.2). In addition, the hydroxyl group
O4-H4 can form hydrogen bond with water and other penicillin sulfoxide molecules.
As a result, the penicillin sulfoxide molecules appear in pairs (Fig.2 left) and 8
molecules are found in a penicillin sulfoxide crystal cell (Fig.2 right). O4-H4 has
great effect on the growth of penicillin sulfoxide just like some similar studies about
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the effects of water on morphology and crystal form
. This group can be used to
explain the special effect of water on penicillin sulfoxide in the following study.
2.2 Morphology simulation
a
A
b
B
c
C
Figure 3. Crystal morphology of penicillin sulfoxide obtained from AE model simulation and
experiments. A, B and C: AE model results in ethyl acetate, butyl acetate and water respectively; a,
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b and c: Grown from ethyl acetate, butyl acetate and water respectively.
The morphology simulation of penicillin sulfoxide is performed by AE model in
Material Studio. Fig.3a, b and c indicate that penicillin sulfoxide grown from ethyl
acetate, butyl acetate and water are display cuboid, bi-pyramidal and plate-like
morphology, respectively. After the morphology simulation of penicillin sulfoxide is
performed by AE model in Material Studio, the results are obtained (Fig.3A, B and C).
The predicted results are well matched with experimental results. Then all the visible
faces are separated from the pure crystal successively, the separated surfaces are used
in binding energy calculation.
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2
.3 Area ratio and binding energy
According to the surface creation method mentioned above, an example of a
separated surface and super cell with solvent molecule are shown in Fig.4.
Figure 4. The separated surface (left) and the super cell with a solvent molecule (right).
After the models are built as shown in Fig.4, the binding energy calculations
results of different solvent molecules adsorbing on the different surfaces of penicillin
sulfoxide are obtained and the surface area of different faces are calculated based on
the crystals obtained from experiments (Fig.3). The area ratio which is the ratio of
each face to the total surface is expressed as a percentage.
Table 2 Binding energy of different solvents on the penicillin sulfoxide crystal surface
Surface
hkl)
Butyl acetate
(kcal/mol)
-24.18
-29.38
-8.99
Ethyl acetate
(kcal/mol)
-14.21
-13.93
-5.25
Water
(kcal/mol)
-0.20
(
0
1
1
1-1
110
-8.25
0-1
-1.27
101
-27.61
-26.51
—
-11.03
-18.66
—
-10.29
-8.49
-10
020
-5.62
0
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02
-32.96
-32.10
-17.58
-24.78
-5.37
-3.91
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The binding energy of different solvent molecules on the penicillin sulfoxide
surfaces is shown in Table 2. The adsorption of one solvent molecule takes place at
the surface. The results shown that the absolute value order of binding energy is butyl
acetate>ethyl acetate>water which indicate that the calculation method gives
reasonable trends for the binding energy.
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A: ethyl acetate
B:butyl acetate
C: water
Figure 5. Bingding energy and area ratio of penicillin sulfoxide grown from different solvents.
In theory, the crystal morphology importance is determined by the faces with
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lower growth rate which will show in the final crystalline produces
. Growth rate
of the faces is the determining factor of the crystal morphology. From Fig.5A and B,
the similar trend that the area ratio always increases with the increasing of binding
energy can be found. The larger the absolute value of binding energy, the larger the
affinity of the adsorbate to the crystal face. Both ethyl acetate and butyl acetate
molecules hinder the adsorption process of penicillin sulfoxide on the specific
surfaces. As a result, the faces with higher binding energy have lower growth rate, and
then the morphology importance of the crystal determined by the faces with higher
binding energy.
Compared with Fig.5A and B, a different trend is shown in Fig.5C. Higher
binding energy always leads to a smaller area ratio. The plate-like morphology of
penicillin sulfoxide grown from water is determined by (002) and (020) (Fig.3c and
C). The formation of hydrogen bond between water and penicillin sulfoxide is the
main factor the special result shown in Fig.5C.
The ability of water molecule forming hydrogen bond with other penicillin
sulfoxide and water molecules is strong. Crystal water molecules are found in the
crystal cell of penicillin sulfoxide shown in Fig.2. As mentioned above, the hydroxyl
group O4-H4 could form hydrogen bond with the water and other penicillin sulfoxide
molecules and it will improve the growth of penicillin sulfoxide.
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Figure 6. Effect of water on induction period of penicillin sulfoxide in butyl acetate.
The effect of water on induction period of penicillin sulfoxide in butyl acetate is
shown in Fig.6. The crystal induction period of penicillin sulfoxide decreases with the
increasing of water content. Solubility of penicillin sulfoxide in water is a little larger
than that in butyl acetate, while the solubility in methylbenzene is much smaller than
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that in butyl acetate . However, the addition of methylbenzene doesn’t reduce the
induction period. As a result, the possibility that water improves the
growth of penicillin sulfoxide crystals is mainly through acting as an anti-solvent
can be excluded. The interaction mechanism of the crystal induction period of
penicillin sulfoxide and water content can be interpreted by the formation of hydrogen
bond. Instead of inhibiting the crystal growth, water could improve the growth of
penicillin sulfoxide crystal. As mentioned before, the larger the absolute value of
binding energy, the larger the affinity of the adsorbate to the crystal face, so the face
with higher binding energy (absolute value) absorbs more water molecules and has a
larger growth rate, then a smaller face is generated. As a result, the area ratio
decreases with the increasing of binding energy.
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2
0
8
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4
2
0
Water
1
Butyl acetate
Ethyl acetate
0.1
1
10
100
1000
ln l
Figure 7. The size distribution of penicillin sulfoxide grown from water, butyl acetate and
ethyl acetate.
The prime crystal size of penicillin sulfoxide obtained from ethyl acetate butyl
acetate and water are 43.2, 95.5 and 251.6μm respectively as shown in Fig.7.
Different solvents also result in different size of penicillin sulfoxide.
Furthermore, the results in Fig.3 and 5 also show that faces (110), (101), (1-10)
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and (020) have smaller surface area than the other 4 faces. The special results are
caused by the space distribution of hydroxyl groups on the different surfaces as shown
in Fig.8.
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interface
Crystal
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110
Figure 8. The space distribution of hydroxyl group O4-H4 at the different interfaces.
In order to explain the structure clearly, the interfaces between vacuum and
crystal face are indicated by dotted lines in Fig.8. As mentioned before, hydroxyl
group O4-H4 could form hydrogen bond with water and other penicillin sulfoxide
molecules which will improve the growth of penicillin sulfoxide. The number of
O4-H4 groups (red points shown in Fig.8) on these 4 faces (list in Fig.8) is about 3-5
while the number is 1-2 on the other 4 faces. Therefore the faces with more O4-H4
groups will have a higher growth rate and less morphology importance.
3
. Experimental section
3
.1 Materials: Penicillin G potassium and penicillin sulfoxide was supplied by North
China of Pharmaceutical Group Corporation Beta Co., Ltd (≥98 %) and refined by
recrystallization ( ≥99%).
3
.2 Crystallization process of penicillin sulfoxide:
The crystalline product of penicillin sulfoxide grown from water is obtained
from acid-base reaction. After penicillin sulfoxide was fully dissolved in water, the
diluted sulfuric acid (2 mol/L) was added at the feeding rate of 0.45 mL/min and the
impeller stirring rate of 200 rpm until the pH value of the solution reached 2.0. After
agitated for 2 h, the crystalline product of penicillin sulfoxide was obtained.
Penicillin sulfoxide grown from butyl acetate and ethyl acetate are obtained by
carrying out the oxidization reaction of penicillin G potassium with peracetic acid as
the oxidizer. After penicillin G potassium was fully dissolved in butyl acetate or ethyl
acetate, the peracetic acid was added and the impeller stirring rate of 300 rpm. Then
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the solution was agitated for 4 h and the crystalline product of penicillin sulfoxide was
obtained.
The morphology of the crystals is measured by scanning electron microscope
(SEM). The size distribution of penicillin sulfoxide crystal grown from water, butyl
acetate and ethyl acetate were determined by Malvern laser particle size
analyzer-Mastersizer 3000.
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3
.3 Single crystal X-ray diffraction: The single crystal X-ray diffraction of
penicillin sulfoxide is carried out on a Rigaku R-axis rapid detector II diffractometer
with Mo Kαradiation (l= 0.71073 Å) at (293.2±2) K. The data collection method is
R-axis rapid IP. SHELXS97 (Sheldrick, 1990) and SHELXL97 (Sheldrick, 1997) are
used to solve and refine the crystal structures.
3
.4 Surface creation and binding energy calculation: Morphology simulation of
penicillin sulfoxide is performed by AE model in Material Studio. All the visible faces
of simulated morphology are separated from the pure crystal successively. Build the
super cell with the separated faces. Then a large region of vacuum above the surface
is created so that the adsorbate can only interact with one of the surfaces. The energy
of the solvent molecule is minimized and the energy of a single solvent molecule (E0)
is calculated. After the adsorbate molecule is docked on the middle of a given surface,
the global minimum energy of the whole system (Es) is obtained. The compass force
field was chosen for the energy expression. The molecule dynamics simulation is
performed under constant number of particles, volume of the cell and temperature
(NVT).
Finally, the molecule dynamics is carried out and the binding energy of a certain
2
8
face (hkl) is calculated by :
E =E -E
(1)
b,hkl
s,hkl
0
In which, Es,hkl is the global minimum energy of the whole system , E is the
0
energy of a single solvent molecule and Eb,hkl is the binding energy of a solvent
molecule on a certain face (hkl).
4. Conclusion
In this paper, binding energy of water, ethyl acetate and butyl acetate molecule
on specific surfaces of penicillin sulfoxide are evaluated. Solvent binding energy on
the specific surfaces was calculated and crystal morphology simulated by AE model
to study the association between binding energy and crystal morphology. Predicted
results are well matched with the experimental results indicating the importance of
solvent binding energy to morphological change of penicillin sulfoxide crystal. Water
has a different effect on the morphology as compared to butyl acetate and ethyl
acetate through hydrogen bond. The technology of solvent effect research using
binding energy simulation has been applied successfully in solvents selection and
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production process optimization . Based on the results of solvents effect on crystal
morphology, the production process is optimized28. By using the strategy developed
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in our study, computer-based simulation and prediction should be proven to be useful
facilitating the future solvent screening.
Acknowledgements
This work has been supported by National Natural Science Foundation of China
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(NSFC 20836005).
Symbols used
E0
[kcal/mol]
the energy of a single solvent molecule
the binding energy of a solvent molecule on a certain face (hkl)
the global minimum energy of the whole system
cell parameter
Eb,hkl
Es,hkl
a,b,c
[kcal/mol]
[kcal/mol]
[Å]
Greek letters
α,ß,γ [°]
cell angle
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