Insight into the Role of Hydrogen Bonding in the ... - ACS Publications

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Insight into the Role of Hydrogen Bonding in the Molecular SelfAssembly Process of Sulfamethazine Solvates Xia Zhang,† Ling Zhou,*,† Chang Wang,† Yang Li,† Yanan Wu,† Meijing Zhang,†,‡ and Qiuxiang Yin*,†,‡ †

School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, and ‡Collaborative Innovation Center of Chemical Science and Chemical Engineering (Tianjin), Tianjin University, Tianjin 300072, People’s Republic of China S Supporting Information *

ABSTRACT: The new solid forms screening of sulfamethazine was conducted in 16 kinds of different pure solvents. Four new sulfamethazine solvates were reported for the first time, and three crystal structures of solvates were successfully determined from single-crystal X-ray diffraction data. The results showed that sulfamethazine solvate formation directly depended on the solvents used in the experiments. The solvent properties were used to evaluate the effects of solvent on solvate formation. It was found that the H-bond acceptor ability of the solvent was the main factor that governed the solvate formation. The H-bonded motifs in the structures of solvates have been fully characterized. The results revealed that sulfamethazine solvate formation was mainly driven by molecular self-assembly through hydrogen bonding between solvent and solute molecules. Meanwhile, the crystal structures results also showed that the sulfamethazine molecule had flexible conformation. Furthermore, the principles of different sulfamethazine molecules packing in different crystal structures were discussed from the view of molecular intermolecular interactions and the molecular conformation.

T

difference in the formation of desirable solvates or polymorphs.9 In practice, it is time-consuming and costly to select a solvent to obtain a desired crystal polymorph or solvate due to lack of appropriate guidance. Meanwhile, it still remains unclear which properties of the solvent act as determinants in the crystallization pathway.10 The object of this work is to investigate the solvent factors which govern the solvate formation and also provide guidelines for choosing an appropriate solvent, which can facilitate or retard solvate formation. Sulfamethazine (or Sulfadimidine) (Figure 1) is widely recognized as an antibacterial drug.8,11,12 Sulfamethazine (SFZ) should has rich conformational flexibility according to its

he phenomenon of polymorph and solvate formation is very common in organic compounds, especially in the active pharmaceutical ingredients (APIs). Different polymorphs and solvates of the APIs may exhibit various physical and chemical properties, which make the screening of the solid form a requisite step in drug production.1,2 Generally, solid forms are screened by changing the kinds of solvents or solvent mixtures and crystallization methods.2 During the solution crystallization, solvates known as crystalline solid adducts may be obtained, whose crystal structure contain both solute and solvent molecules.3,4 To control the phase of the crystalline product, it is significant to figure out which is the prerequisite condition to form a specific solvate. Generally, crystal engineering mainly focuses on how to design novel solids with different physicochemical properties on the basis of understanding of intermolecular interactions in crystal packing.5 A crystal was viewed as a supramolecular entity created from structural synthons or molecular building blocks, which was defined as a recurring hydrogen bond and/or intermolecular interaction pattern of molecules.6,7 For obtaining new forms of APIs, especially in the cocrystal area, the crystal engineering method is treated as an effective route to select coformers for obtaining prescient structures based on the synthon approach.8 In fact, the supramolecular assembly process of a cocrystal is essentially similar to that of a solvate; thus, the crystal engineering approach may also be a successful design strategy for obtaining newly desired solvates of the drug. In the solution crystallization, APIs with multiple hydrogen bonding functionalities have a strong possibility to form solvates. Therefore, a correct selection of solvent may make a © 2017 American Chemical Society

Figure 1. Chemical structure of sulfamethazine. Received: May 22, 2017 Revised: September 13, 2017 Published: September 26, 2017 6151

DOI: 10.1021/acs.cgd.7b00717 Cryst. Growth Des. 2017, 17, 6151−6157

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chemical structure, and there are various strong hydrogen bonding groups including −SO2−, −NH−, and −NH2 which favor them to form different solvates and solid forms.11 To date, only the single crystal XRD data of SFZ (Form I) has been reported.13,14 In addition, SFZ can form cocrystals with carboxylic acids and amides.8,15,16 Among all of these cocrystals, heterodimers can be formed through a intermolecular hydrogen-bonding motif. In this study, a crystal form screening of SFZ was realized by selecting the common solvents with different classes. Meanwhile, the relationship between solvate appearance and solvent was also investigated by analyzing the interplay between API and solvent molecules from the single crystal data. The structures of these solvates were visually compared by use of Hirshfeld surface analysis. A crystal form screening of SFZ is conducted in 16 kinds of commonly used solvents which cover different solvent classes (Supporting Information). The solvents for screening and the obtained crystal forms are listed in Table 1. It can be seen that,

Figure 2. PXRD patterns of the sulfamethazine solvates and polymorph form I.

Table 1. Properties of the Solvents and the Solvate Formation solvent

α

β

π*

observed form of SFZ

N-methyl pyrrolidone N,N-dimethylacetamide N,N-dimethylformamide dimethyl sulfoxide formamide acetone ethanol n-propanol i-propanol n-butanol i-butanol ethyl formate methyl acetate ethyl acetate propyl acetate acetonitrile

00 00 00 00 71 08 86 84 76 84 79 00 00 00 00 19

77 76 69 76 48 43 75 90 84 84 84 36 42 45 40 40

92 88 88 100 97 71 54 52 48 47 40 61 60 55

solvate solvate solvate solvate Form I Form I Form I Form I Form I Form I Form I Form I Form I Form I Form I Form I

75

solvates is calculated. The results demonstrate that all the solvates should be monosolvate. From Table 1, it can clearly be seen that solvates of sulfamethazine (SFZ) are preferred in amide solvents and dimethyl sulfoxide. Solvates are obtained in DMF, DMA, and NMP. However, solvate is not obtained from formamide, whose chemical structure also contains the functional group of −CONH2. In addition, the solvate can be formed in DMSO solvent, whose molecular structure did not contain the functional group −CONH2. By comparing the structures of the solvents (Figure 4), it can be concluded that the similar structure is not the key factor for the formation of solvate. As mentioned by the crystal engineering approach, the solute molecules combine with the solvent molecules for the solvated, and then they assemble into various motifs in solution, which are referred to as growth synthons.6 The formation of growth synthons relate to the solvent−solute interaction, which can be evaluated through hydrogen bonding and van der Waals force. Thus, it can be speculated that the observed solvates should be related to the properties of the solvents used. According to the literature,18,19 the H-bond donor ability α and H-bond acceptor ability β can be used to evaluate the strength of H-bonding between the solvent and the solute. The dipolar polarizability (π*) can be used to evaluate the strength of van der Waals interactions between the solvent and the solute. The values of α, β, and π*of different solvents applied in the crystallization are also concluded in Table 1. For the solvents that can form solvates, the α values of the solvents are close to 0. Meanwhile, β and π* values are very high. In solvents whose α values are not close to 0 and β and π* values are lower than 70, solvates tend not to be produced. It seems that both the hydrogen bond acceptor ability and dipolar polarizability affect the solvates formation of SFZ. From Table 1, the solvents which can form solvates have big values of π*. Meanwhile, the solubility of SFZ in these solvents is also bigger than that of those which could not form solvates. This can be explained by the principle of “like dissolves like”. The higher the β value, the stronger the hydrogen bond acceptor ability is. This can be explained by the molecular structures of SFZ, which have a high propensity to donate protons to form a hydrogen bond with solvents. From Figure 1, SFZ has two kinds of donors including amine (−NH2) and imine (−NH−), which possess three acidic protons. Then the bigger the β

besides the already known polymorphic form I, four new crystalline forms are obtained from N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methyl pyrrolidone (NMP), and dimethyl sulfoxide (DMSO). PXRD measurement and thermal methods were applied to detect the obtained new crystal forms. It was found that all the new crystal forms should be assigned to SFZ solvates, which were labeled as SFZ-DMF, SFZ-DMA, SFZ-NMP, and SFZ-DMSO, respectively. PXRD patterns of the four obtained SFZ solvates are shown in Figure 2. The diffraction peak positions of SFZ-DMF, SFZDMA, SFZ-NMP, and SFZ-DMSO are clearly different with the known SFZ form I. However, the PXRD patterns of SFZDMA and SFZ-NMP are very similar, which suggests that these two solvated forms should be isostructural.17 The DSC and TGA curves of SFZ solvates are shown in Figure 3 and Table 2. It is noteworthy that endothermic peaks and mass loss can be observed as the temperature is less than 140 °C. The obvious endothermic peak at about 197 °C should be ascribed to the melting peak for the desolvated product. From the weight loss in TG curves, the stoichiometry of the 6152



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Figure 3. DSC and TGA curves of sulfamethazine solvates: (a) SFZ-DMF solvate; (b) SFZ-DMA solvate ; (c) SFZ-NMP solvate; (d) SFZ-DMSO solvate.

hydrogen bond acceptor abilities can lead to the formation of SFZ solvates. However, the crystal structure analysis is necessary to investigate the hydrogen bonding preferences of acceptors and donors if competitive functional groups exist. The crystallographic data of SFZ-DMF, SFZ-DMA, and SFZNMP solvates were measured (Supporting Information). Meanwhile, the crystal structure of SFZ form I was retrieved from the Cambridge Structural Database (CSD Refcodes: SLFNMD10).14 The obtained crystallographic data are given in Tables 3. The crystal structure of the SFZ assigns to the monoclinic P21/c space group, and a periodic H-bonding motif can be seen in SFZ (Figure 5a). A single intermolecular hydrogen bond (N−H···O) between H atom in imino groups and O atom in sulfonyl group is formed (Figure S1, Table S1, Supporting Information). The asymmetric unit of SFZ-DMF solvate is composed of SFZ solute and DMF solvent. Its crystal structure assigns to the monoclinic P21/n space group. There are mainly two kinds of hydrogen bonds: one is formed by the hydrogen atom in the amine bonding with one sulfonyl oxygen atom of an adjacent

Table 2. Weight Loss Observed during the Desolvation of SFZ Solvates solvate

ratio

calculated weight loss, %

SFZ-DMF solvate SFZ-DMA solvate SFZ-NMP solvate SFZDMSO solvate

1:1

20.80%

20.79%

108.08

196.57

1:1

23.84%

24.10%

93.89

197.92

1:1

26.26%

25.24%

123.17

197.96

1:1

21.92%

20.89%

81.75, 131.44a

196.25

measured mass loss, %

Tdesolvation, °C (peak)

Tmelting, °C (peak)

a

Two endothermic peaks appear during the desolvation process on the DSC curve.

values of the solvents, the more easily solvates can be crystallized eventually. Therefore, it can be speculated that the effects of solvent on solvate formation of SFZ are mainly reflected through the H-bonding interactions between the solvent and solute molecules, and increment of the solvents’

Figure 4. Molecular structures of the solvents used for solvates investigated herein. 6153



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Table 3. Crystallographic Data for SFZ form I and SFZ Solvates (SFZ-DMF, SFZ-DMA, and SFZ-NMP)

a

phase

SFZ form Ia

SFZ-DMF

SFZ-DMA

SFZ-NMP

Empirical formula Formula weight Crystal system space group a (Å) b (Å) c (Å) Volume(Å3) Z Z′ R1 (%) goodness-of-fit

C12H14N4O2S 278.33 monoclinic P21/c 9.27(1) 18.94(2) 7.46(1) 1299.16 1 0.25 n/a n/a

C12H14N4O2S·C3H7NO 351.43 monoclinic P21/n 9.4267(19) 13.851(3) 14.619(3) 1808.1(6) 4 1 6.73 1.038

C12H14N4O2S·C4H9NO 365.45 monoclinic P21/n 13.408(3) 10.874(2) 25.595(5) 3642.1(13) 8 2 5.61 0.91

2(C12H14N4O2S)·2(C5H9NO) 754.93 monoclinic P21/n 13.218(3) 11.009(2) 25.835(5) 3664.4(13) 4 1 4.49 1.098

Crystal structure of the sulfamethazine form I was retrieved from the Cambridge Structural Database (CSD Refcodes: SLFNMD10).

Figure 5. Crystal packing in different crystal structures: (a) SFZ form I, (b) SFZ-DMF solvate, (c) SFZ-DMA solvate, (d) SFZ-NMP solvate.

SFZ molecule (Figure 5b); the other is formed by oxygen atom of DMF bonding with the hydrogen atom in the imine of the SFZ molecule (Figure S2, Table S2, Supporting Information). The crystal structure of SFZ-DMA solvate is ascribed to the monoclinic P21/n space group. In each asymmetric unit, there are four molecules, including two SFZ and two DMA molecules. Compared with SMF form I, the recurring hydrogen bonding motif between molecules of SFZ is disappeared in this crystal structure (Figure 5c). One kind of N−H···O hydrogen bonding is formed by the oxygen atom of the DMA molecule bonding with one H atoms from amine group (−NH2) in one SFZ molecule. Meanwhile, the oxygen atom of the DMA molecule is also form hydrogen bonding with the H atom from imine groups (−NH−) of the adjacent SFZ molecules. In each asymmetric unit, a DMA molecule is disordered (Figure S3, Supporting Information). The single crystal XRD operated at low temerature of 100 K result shows that the disorder modeling of the DMA molecule occupy two separate sites with 54.8% and 45.2% occupancy factors, respectively. As shown in Table 3, crystallographic data of SFZ-DMA and SFZ-NMP solvates illustrate that they are isostructural solvates. Crystals of the NMP solvate of SFZ belong to the monoclinic P21/n space group, and two SFZ and two NMP molecules constitute the asymmetric unit. Similar to DMA solvate of SFZ, two kinds of N−H···O hydrogen bonds are formed by the oxygen atom of the NMP molecule bonding with one amine

group (−NH2) of the SFZ molecule and the imine (−NH−) group of adjacent SFZ molecule (Figure 5d). However, the two NMP molecules are disorder in the asymmetric unit (Figure S4, Supporting Information). One NMP molecule occupies two separate sites with the occupancy factors of 54.7% and 45.3%, respectively. The other NMP molecule exhibits two separate sites, whose occupancy factors are 29.23% and 70.77%, respectively. The analysis reveals that all the crystal structures contain N− H···O synthon. The solvents with strong hydrogen bond acceptor ability can form hydrogen bonding with the amine and imine, and then the SFZ solvate are formed. Therefore, SFZ solvate formation is mainly driven by molecular self-assembly through hydrogen bonding between solute and solvent molecules. Compared with SMF form I, the hydrogen bonded motifs are quite distinct because of the existence of the solvents. Thus, the formation of different H-bonds also plays an important role on the obvious difference of SFZ molecules packing in the solid state. According to the literature,20 the different molecular conformation of flexible molecules may also lead to the changes of molecular packing. The chemical structure of SFZ (Figure 1) suggests that the conformation differences of SFZ molecules in different forms should be due to different values of the dihedral angles τ1 (C2C1S1N2), τ2 (C1S1N2C7), and τ3 (S1N2C7N3). Indeed, as shown in Table 4 and Figure 6, the 6154



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Table 4. Dihedral Angles (in Degrees) of SFZ in SFZ Form I and Its Solvates τ1 τ2 τ3

SFZ Form I

SFZ-DMF

SFZ-DMA(A)

SFZ-DMA(B)

SFZ-NMP(A′)

SFZ-NMP(B′)

−55.02 −84.85 −148.34

−121.8 61.4 2.9

43.2 67.2 167.5

110.3 −63.1 13.1

47.1 67.5 166.8

113.9 −64.9 13.2

Figure 6. Overlay of SFZ molecules in SFZ Form I and solvates.

single crystal XRD data reveal that the conformations of SFZ molecules in various solid states are different. Interestingly, the molecules conformations of SFZ in three solvates are quite different that in SFZ Form I. It can be concluded that SFZ molecule has flexible molecular conformation. As mentioned already, the molecular conformation of SFZ (A and A′ molecules, B and B′ molecules) in SFZ-DMA and SFZ-NMP solvates are quite similar, which further illustrates that they are isostructural solvates. According to the different solvents and their self-assembly in the solvate structures, it can be concluded that the different SFZ molecules conformation lead to different hydrogen bond networks in the solvates.11 Therefore, the molecular conformations also make a difference in molecular packing in solid state. Hirshfeld surfaces and fingerprint plots of the SFZ molecule in different crystal environment are also powerful tools for elucidating and comparing similarities and differences.21 Hirshfeld surfaces for SFZ molecule in different forms are shown in Figure 7 respectively. All independent SFZ molecules exhibit different Hirshfeld surfaces shapes, which reflect various packing motifs and intermolecular arrangements in the solid state. The dnorm surface is shown as transparent, which allows the SFZ group be visible and highlights acceptor and donor equally. The data presented in Tables S1−S4 is concluded and plotted in Figure 7. The deeply red and large circular depressions on the surfaces indicate the H-bonding contacts. In addition, the Hirshfeld 2D-fingerprint plots provide more information about the intermolecular interactions. Fingerprint plots can reflect the unique polymorphic form of molecule due to its high sensitivity to the immediate environment of the molecule. 2D-fingerprint plots from Hirshfeld surface analyses of SFZ molecule in different forms are also shown in Figure 7 respectively. It can be seen that the 2D-fingerprint plots of SFZ Form I are quite different from those obtained from three solvates, which are affected by the interaction between solute and solvent molecules. For a better comparison, the particularly close contacts are decomposed by fingerprint plots. Figure 8 exhibits the relative contributions due to close contacts of H···H, H···O, H···N, H··· C (i.e., C−H···π), and C···C (i.e., π···π) for Hirshfeld surface area of SFZ molecule in different crystal forms.

Figure 7. Hirshfeld surfaces and 2D-fingerprint plots of SFZ molecule in Form I, and SFZ-DMF, SFZ-DMA, and SFZ-NMP solvates, respectively.

Importantly, the intermolecular H···H bonding in all forms seems to be a main factor in the crystal packing, which makes up 42.2% to 56.4% of the Hirshfeld surface of these molecules. These contacts are mainly due to the interaction of methyl groups with protons from neighboring molecules. The results also show that the proportions of H···O interactions are similar for all the forms, which constitute the main hydrogen bonded networks in different crystal structures. It immediately emerges that all proportions of close contacts are almost the same for the SFZ molecule with similar conformation in the isostructural SFZ-DMA and SFZ-NMP solvates. However, the obvious difference are observed in the proportions of H···C and C···C interactions in SFZ-DMF solvate. It can be seen that there is a 6155



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Major National Scientific Instrument Development Project (No. 21527812), and Natural Science Foundation of Tianjin (No. 16JCZDJC32700).

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(1) Berziņ ̅ s,̌ A.; Skarbulis, E.; Rekis, T.; Actiņs,̌ A. On the Formation of Droperidol Solvates: Characterization of Structure and Properties. Cryst. Growth Des. 2014, 14 (5), 2654−2664. (2) Braun, D. E.; Gelbrich, T.; Kahlenberg, V.; Griesser, U. J. Solid state forms of 4-aminoquinaldine - From void structures with and without solvent inclusion to close packing. CrystEngComm 2015, 17 (12), 2504−2516. (3) Zhang, X.; Yin, Q.; Du, W.; Gong, J.; Bao, Y.; Zhang, M.; Hou, B.; Hao, H. Phase Transformation between Anhydrate and Monohydrate of Sodium Dehydroacetate. Ind. Eng. Chem. Res. 2015, 54 (13), 3438−3444. (4) Takieddin, K.; Khimyak, Y. Z.; Fábián, L. Prediction of Hydrate and Solvate Formation Using Statistical Models. Cryst. Growth Des. 2016, 16 (1), 70−81. (5) Desiraju, G. R. Crystal engineering: the design of organic solids (Materials Science Monographs); Elsevier, 1989. (6) Chen, J.; Trout, B. L. Computational study of solvent effects on the molecular self-assembly of tetrolic acid in solution and implications for the polymorph formed from crystallization. J. Phys. Chem. B 2008, 112 (26), 7794−802. (7) Reddy, L. S.; Babu, N. J.; Nangia, A. Carboxamide-pyridine Noxide heterosynthon for crystal engineering and pharmaceutical cocrystals. Chem. Commun. 2006, 13, 1369−71. (8) Ghosh, S.; Bag, P. P.; Reddy, C. M. Co-Crystals of Sulfamethazine with Some Carboxylic Acids and Amides: Co-Former Assisted Tautomerism in an Active Pharmaceutical Ingredient and Hydrogen Bond Competition Study. Cryst. Growth Des. 2011, 11 (8), 3489−3503. (9) Mirmehrabi, M.; Rohani, S. An approach to solvent screening for crystallization of polymorphic pharmaceuticals and fine chemicals. J. Pharm. Sci. 2005, 94 (7), 1560−76. (10) Gu, C. H.; Young, V.; Grant, D. J. W. Polymorph screening: Influence of solvents on the rate of solvent-mediated polymorphic transformation. J. Pharm. Sci. 2001, 90 (11), 1878−1890. (11) Aitipamula, S.; Chow, P. S.; Tan, R. B. H. The solvates of sulfamerazine: structural, thermochemical, and desolvation studies. CrystEngComm 2012, 14 (2), 691−699. (12) Tailor, S. M.; Patel, U. H. Hirshfeld surface analysis of sulfameter (polymorph III), sulfameter dioxane monosolvate and sulfameter tetrahydrofuran monosolvate, all at 296 K. Acta Crystallogr., Sect. C: Struct. Chem. 2015, 71, 944−53. (13) Tiekink, E. R. T.; Arman, H. D.; Kaulgud, T. 1:1 Co-crystals of sulfadimidine with three bipyridine-type molecules: Persistence of N− H···N hydrogen bonded supramolecular chains. Z. Kristallogr. - Cryst. Mater. 2014, 229 (5), 1 DOI: 10.1515/zkri-2013-1706. (14) Tiwari, R. K.; Haridas, M.; Singh, T. P. Structure of 4-amino- N -(4,6-dimethyl-2-pyrimidinyl)benzenesulphonamide (sulfadimidine), C12 H14 N4O2S. Acta Crystallogr. 1984, 40 (4), 655−657. (15) Lu, J.; Cruz-Cabeza, A. J.; Rohani, S.; Jennings, M. C. A 2:1 sulfamethazine-theophylline cocrystal exhibiting two tautomers of sulfamethazine. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2011, 67, o306−9. (16) Arman, H. D.; Kaulgud, T.; Tiekink, E. R. 4-Amino-N-(4,6-dimethyl-pyrimidin-2-yl)benzene-sulfonamide-1,4-di-aza-bicyclo-[2 0.2.2]octane (2/1). Acta Crystallogr., Sect. E: Struct. Rep. Online 2013, 69, o1615. (17) Berziņ ̅ s,̌ A.; Skarbulis, E.; Actiņs,̌ A. Structural Characterization and Rationalization of Formation, Stability, and Transformations of Benperidol Solvates. Cryst. Growth Des. 2015, 15 (5), 2337−2351. (18) Du, W.; Yin, Q.; Gong, J.; Bao, Y.; Zhang, X.; Sun, X.; Ding, S.; Xie, C.; Zhang, M.; Hao, H. Effects of Solvent on Polymorph Formation and Nucleation of Prasugrel Hydrochloride. Cryst. Growth Des. 2014, 14 (9), 4519−4525.

Figure 8. Relative contributions of the SFZ molecule to the Hirshfeld surface area for the various close intermolecular contacts.

bigger proportion of H···C interactions in SFZ-DMF solvate than other forms, and there is no C···C interaction. As shown in Figure 5a and c, intermolecular π···π interactions are observed between the centroids of the two pyrimidine rings. There are no intermolecular π···π interactions according to SFZ-DMF molecular packing (Figure 5b). Therefore, weak intermolecular interactions also lead to the changes of molecular packing in the solid state.20 In summary, the solvate formation of sulfamethazine was studied in this work. It was found that SFZ solvate formation was mainly driven by molecular self-assembly through hydrogen bonding between solute and solvent molecules. Meanwhile, the hydrogen bond acceptor ability of the solvent mainly determines the formation of intermolecular hydrogen bonds. It was confirmed that SFZ molecule had conformational flexibility. Besides, different molecular packing in the solid state was controlled by the formation of hydrogen bonds, the differences in the molecular conformation and also other weak intermolecular interactions.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.7b00717. Tables of D−H···A distances for H-bonds data are available for structures of sulfamethazine solvates (PDF) Accession Codes

CCDC 1552235−1552236 and 1552244 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/ cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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REFERENCES

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Qiuxiang Yin: 0000-0001-8812-0848 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors are grateful for the financial support of the National Natural Science Foundation of China (21676179), the 6156



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(19) Marcus, Y. ChemInform Abstract: The Properties of Organic Liquids that are Relevant to Their Use as Solvating Solvents. Cheminform 1993, 25 (12), 409−416. (20) Be̅rziņ s ,̌ A.; Actiņ s ,̌ A. Why Do Chemically Similar Pharmaceutical Molecules Crystallize in Different Structures: A Case of Droperidol and Benperidol. Cryst. Growth Des. 2016, 16 (3), 1643− 1653. (21) Wolff, S. K.; Grimwood, D. J.; McKinnon, J. J.; Turner, M. J.; Jayatilaka, D.; Spackman, M. A. CrystalExplorer3.0; University of Western Australia, 2013; http://hirshfeldsurface.net.

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