Study on Crystal Morphology of Penicillin Sulfoxide in Different

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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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Organic Process Research & Development

Study on Crystal Morphology of Penicillin Sulfoxide in Different Solvents Using Binding Energy Dingding Jing1, Ailing Liu1, Jingkang Wang2, Huiming Xia3* 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: [email protected]. 1

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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.

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.

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 bioavailability1. 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 methods2-8 (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 theories9-12 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. Based on the second theory, the prediction model of crystals induced by additives was developed13 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 used to produce 7-amido-3-methyl-3-cephem-4-carboxylic acid (7-ADCA) by catalytic 14-18 ring-enlargement and enzymatic hydrolysis reaction and 7-ADCA is one of the most important nucleuses of cephalosporin antibiotic.

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, bioavailability, hardness and appearance19,20. As a result, a detailed investigation on 4


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the solvent effect on penicillin sulfoxide is necessary. By using Material Studio, the binding energy calculation and morphology simulation were carried out with Attachment Energy (AE) model21,22 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. 2. Results and Discussion 2.1 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. Formula crystal system space groups cell parameter (Å)

cell angle(°)

cell volume /Å3 Z calculated density /g/cm3

XRD results

Structure minimization

C16H18N2O5S·1.5H2O orthorhombic P212121 a = 8.413 b = 19.133 c = 23.116 α = 90.00° ß = 90.00° γ = 90.00° 3721 8 1.335

C16H18N2O5S·1.5H2O orthorhombic P212121 a = 7.936 b = 18.586 c = 22.542 α = 90.00° ß = 90.00° γ = 90.00° 3325 8 1.494

Penicillin sulfoxide belongs to orthorhombic system. The space group is P212121, and there are 1.5 water molecules around one penicillin sulfoxide on average 23. 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 the effects of water on morphology and crystal form13,24. 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, 6


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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. 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)

Ethyl acetate (kcal/mol)

Water (kcal/mol)

01-1 110 10-1 101 1-10 020 011 002

-24.18 -29.38 -8.99 -27.61 -26.51 — -32.96 -32.10

-14.21 -13.93 -5.25 -11.03 -18.66 — -17.58 -24.78

-0.20 -8.25 -1.27 -10.29 -8.49 -5.62 -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.

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 lower growth rate which will show in the final crystalline produces25,26. 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 that in butyl acetate27. 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. Volume fraction(%)

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12 Water

10

Butyl acetate

8

Ethyl acetate

6 4 2 0 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) 9



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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.

Vacuum

interface

Crystal

1-10

020

101

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 10


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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. 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 face (hkl) is calculated by28:

Eb,hkl=Es,hkl-E0

(1)

In which, Es,hkl is the global minimum energy of the whole system , E0 is the 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 production process optimization29. Based on the results of solvents effect on crystal morphology, the production process is optimized28. By using the strategy developed 11



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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 (NSFC 20836005). Symbols used E0

[kcal/mol] Eb,hkl [kcal/mol] Es,hkl [kcal/mol] a,b,c [Å] Greek letters α,ß,γ [°]

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 cell angle

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Study on Crystal Morphology of Penicillin Sulfoxide in Different

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