Insight into the Role of Hydrogen Bonding in the Molecular Self

Subscriber access provided by Purdue University Libraries

Communication

Insight into the role of hydrogen bonding playing in the molecular self-assembly process of sulfamethazine solvates Xia Zhang, Ling Zhou, Chang Wang, Yang Li, Yanan Wu, Meijing Zhang, and Qiuxiang Yin Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b00717 • Publication Date (Web): 26 Sep 2017 Downloaded from http://pubs.acs.org on September 27, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Crystal Growth & Design is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

Insight into the role of hydrogen bonding playing in the molecular self-assembly process of sulfamethazine solvates Xia Zhang†, Ling Zhou†, *, Chang Wang†, Yang Li†, Yanan Wu†, Meijing Zhang†, ‡, Qiuxiang Yin†, ‡, * †School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, Tianjin University, and ‡ Collaborative Innovation Center of Chemical Science and Chemical Engineering (Tianjin), Tianjin 300072, People's Republic of China *E-mail: [email protected], [email protected] ; Phone: 86-22-27405754; Fax: 86-22-27314971

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 solvates 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.

ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The phenomena of polymorphs and solvates formation are 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 solid form is a requisite step in the 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 recurring hydrogen bond and/or intermolecular interaction patterns of molecules.6,7 For obtaining new forms of APIs, especially in co-crystal area, the crystal engineering method is treated as an effective route to select co-formers for obtaining prescient structures based on the synthon approach.8 In fact, the supramolecular assembly process of a co-crystal is essentially similar to that of a solvate, thus the crystal engineering approach may be also a successful design strategy for obtaining new desired solvates of the drug. In the solution crystallization, APIs with multiple hydrogen bonding functionalities have a strong possibility to form solvates. Therefore, a right selection of solvent may make difference on the formation of desirable solvates or polymorph.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 solvates formation and also provide guideline for choosing an appropriate solvent, which can facilitate or to retard solvates formation. Sulfamethazine (or Sulfadimidine) (Fig. 1) is widely recognized as antibacterial drug.8,


Page 2 of 25

Page 3 of 25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


11-12

Sulfamethazine (SFZ) should has rich conformational flexibility according to its

chemical structure, and there are various strong hydrogen bonding groups including -SO2-, -NH- and -NH2 which favour 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 co-crystals with carboxylic acids and amides.8, 15-16 Among all of these co-crystals, 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 solvates appearance and solvents was also investigated by analyzing the interplay between API and solvent molecules from the single crystal data. And 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 covering different solvent classes (Supporting Information). The solvents for screening and the obtained crystal forms are concluded in Table 1. It can be seen that, 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), dimethyl sulfoxide (DMSO). PXRD measurement and thermal methods were applied to detect the obtained new crystal forms. It was found the 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, SFZ-DMA, SFZ-NMP and SFZ-DMSO are clearly different with the known SFZ form I. However, the PXRD patterns of SFZ-DMA and SFZ-NMP are very similar, which suggesting 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



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

stoichiometry of the solvates is calculated. The results demonstrate that all the solvates should be monosolvate. From Table 1, it can be clearly seen that solvates of sulfamethazine (SFZ) are preferred in amides 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. What’s more, the solvate can be formed in DMSO solvent, whose molecular structure not contained 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 crystal engineering approach, the solute molecules combine with the solvent molecules for the solvated, then they assemble into various motifs in solution, which are referred 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 used solvents Properties. According to the literatures,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 which 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, 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 are also bigger than that could not form solvates. This can be explained by the principle of “like dissolve like”. The higher the β value, the stronger the hydrogen bond acceptor ability. 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


Page 4 of 25

Page 5 of 25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


donors including a amine (-NH2) and a imine (-NH-), which totally possess three acidic protons. Then the bigger the β values of the solvents, the more easily solvates can be crystallized eventually. Therefore, it can be speculated that the effects of solvent on solvates formation of SFZ are mainly reflected through the H-bonding interactions between the solvent and solute molecules, and increment of the solvents’ 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 competition functional groups exist. The crystallographic data of SFZ-DMF, SFZ-DMA and SFZ-NMP 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 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



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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, 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 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


Page 6 of 25

Page 7 of 25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


solvates are quite different that in SFZ Form I. It can be concluded that SFZ molecule has flexible molecular conformation. As aforementioned, 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 difference on 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 Fig. 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 SFZ group be visible and highlights acceptor and donor equally. The data presented in Tables S1-S4 is concluded and plotted in Fig. 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 Fig. 7 respectively. It can be seen that the 2D-fingerprint plots of SFZ Form I is quite different with that obtained from three solvates, which are affected by the interaction between solute and solvent molecules. For a better comparison, the particular close contacts are decomposed by fingerprint plots. Fig. 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. 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



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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 conformational 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 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 Figure 5c, intermolecular π…π interactions are observed between the centroids of the two pyrimidine ring. There is 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 solvates 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.

■ ACKNOWLEDGEMENTS The authors are grateful for the financial support of the National Natural Science Foundation of China (21676179), the Major National Scientific Instrument Development Project (No. 21527812), and Natural Science Foundation of Tianjin (No. 16JCZDJC32700). ■ SUPPORTING INFORMATION X-ray crystallographic information files (CIF) and tables of D−H···A distances for


Page 8 of 25

Page 9 of 25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


H-bonds data are available for structures of sulfamethazine solvates. This information is available free of charge via the Internet at http: //pubs.acs.org ■ REFERENCES 1. Be̅rziņš, A.; Skarbulis, E.; Rekis, T.; Actiņš, 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, 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 N-oxide 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.; Jr, V. Y.; 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 Cryst., 2015, 71 (Pt 11), 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. Zeitschrift für Kristallographie - Crystalline Materials 2014, 229 (5). 14. Tiwari, R. K.; Haridas, M.; Singh, T. P., Structure of 4-amino- N



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

-(4,6-dimethyl-2-pyrimidinyl)benzenesulphonamide (sulfadimidine), C12 H14 N4O2S. Acta Cryst., 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 Cryst., 2011, 67, o306-9. 16. Arman, H. D.; Kaulgud, T.; Tiekink, E. R., 4-Amino-N-(4,6-di-methyl-pyrimidin-2-yl)benzene-sulfonamide-1,4-di-aza-bicyclo-[ 2 .2.2]octane (2/1). Acta Cryst., 2013, 69, o1615. 17. Be̅rziņš, A.; Skarbulis, E.; Actiņš, 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. 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. Be̅rziņš, A.; Actiņš, 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 (2013), University of Western Australia. http://hirshfeldsurface.net.


Page 10 of 25

Page 11 of 25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure captions: Figure 1. Chemical structure of sulfamethazine. Figure 2. PXRD patterns of the sulfamethazine solvates and polymorph form I. 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. Figure 4. Molecular Structures of the solvents Used for solvates investigated herein. Figure 5. Crystal packing in different crystal structures: (a) SFZ form I, (b) SFZ-DMF solvate, (c) SFZ-DMA solvate, (d) SFZ-NMP solvate. Figure 6. An overlay of SFZ molecules in SFZ Form I and solvates. Figure 7. Hirshfeld surfaces and 2D-fingerprint plots of SFZ molecule in Form I, and SFZ-DMF, SFZ-DMA and SFZ-NMP solvates respectively. Figure 8. Relative contributions of the SFZ molecule to the Hirshfeld surface area for the various close intermolecular contacts.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 1. Chemical structure of sulfamethazine.

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

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.


Page 12 of 25

Page 13 of 25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 4. Molecular Structures of the solvents Used for solvates investigated herein.

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

Figure 6. An overlay of SFZ molecules in SFZ Form I and solvates.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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

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


Page 14 of 25

Page 15 of 25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 1. Properties of the Solvents and the Solvates Formation Observed form of SFZ

solvent

α

β

ߨ∗

N-methyl pyrrolidone

00

77

92

solvate

N,N-dimethylacetamide

00

76

88

solvate

N,N-dimethylformamide

00

69

88

solvate

dimethyl sulfoxide

00

76

100 solvate

formamide

71

48

97

Form I

acetone

08

43

71

Form I

ethanol

86

75

54

Form I

n-propanol

84

90

52

Form I

i-propanol

76

84

48

Form I

n-butanol

84

84

47

Form I

i-butanol

79

84

40

Form I

ethyl formate

00

36

61

Form I

methyl acetate

00

42

60

Form I

ethyl acetate

00

45

55

Form I

propyl acetate

00

40

acetonitrile

19

40

Form I 75

Form I

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

ratio

calculated weight loss, %

measured mass loss, %

SFZ-DMF solvate

1:1

20.80 %

20.79 %

Tdesolvation, °C (peak) 108.08

Tmelting, °C (peak) 196.57

SFZ-DMA solvate

1:1

23.84 %

24.10 %

93.89

197.92

SFZ-NMP solvate

1:1

26.26 %

25.24 %

123.17

197.96

SFZ-DMSO solvate

1:1

21.92 %

20.89 %

81.75, 131.44a

196.25

a

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



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 25

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

Phase

Empirical formula

SFZ form Ia

SFZ-DMF

C12H14N4O2S C12H14N4O2S·C3H7NO

SFZ-DMA

SFZ-NMP

C12H14N4O2S·C4H9NO

2(C12H14N4O2S)·2(C5H9NO)

Formula weight

278.33

351.43

365.45

754.93

Crystal system

monoclinic

monoclinic

monoclinic

monoclinic

space group

P21/c

P21/n

P21/n

P21/n

a (Å)

9.27(1)

9.4267(19)

13.408(3)

13.218(3)

b (Å)

18.94(2)

13.851(3)

10.874(2)

11.009(2)

c (Å)

7.46(1)

14.619(3)

25.595(5)

25.835(5)

Volume(Å3)

1299.16

1808.1(6)

3642.1(13)

3664.4(13)

Z

1

4

8

4

Z'

0.25

1

2

1

R1 (%)

n/a

6.73

5.61

4.49

goodness-of-fit

n/a

1.038

0.91

1.098

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

Table 4. Dihedral Angles (in Degrees) of SFZ in SFZ Form I and its solvates SFZ Form I

SFZ-DMF

SFZ-DMA(A)

SFZ-DMA(B)

SFZ-NMP(A’)

SFZ-NMP(B’)

τ1

-55.02

-121.8

43.2

110.3

47.1

113.9

τ2

-84.85

61.4

67.2

-63.1

67.5

-64.9

τ3

-148.34

2.9

167.5

13.1

166.8

13.2


Page 17 of 25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


For Table of Contents Use Only

Insight into the role of hydrogen bonding playing in the molecular self-assembly process of sulfamethazine solvates Xia Zhang†, Ling Zhou†, *, Chang Wang†, Yang Li†, Yanan Wu†, Meijing Zhang†, ‡, Qiuxiang Yin†, ‡, * †School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, Tianjin University, and ‡ Collaborative Innovation Center of Chemical Science and Chemical Engineering (Tianjin), Tianjin 300072, People's Republic of China *E-mail: [email protected], [email protected] ; Phone: 86-22-27405754; Fax: 86-22-27314971

TOC graphic

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 solute and solvent molecules.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 1. Chemical structure of sulfamethazine. 39x34mm (300 x 300 DPI)


Page 18 of 25

Page 19 of 25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 2. PXRD patterns of the sulfamethazine solvates and polymorph form I. 82x63mm (300 x 300 DPI)



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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. 82x57mm (300 x 300 DPI)


Page 20 of 25

Page 21 of 25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 4. Molecular Structures of the solvents Used for solvates investigated herein. 934x160mm (95 x 95 DPI)



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 5. Crystal packing in different crystal structures: (a) SFZ form I, (b) SFZ-DMF solvate, (c) SFZ-DMA solvate, (d) SFZ-NMP solvate. 82x44mm (300 x 300 DPI)


Page 22 of 25

Page 23 of 25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 6. An overlay of SFZ molecules in SFZ Form I and solvates. 82x34mm (300 x 300 DPI)



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 7. Hirshfeld surfaces and 2D-fingerprint plots of SFZ molecule in Form I, and SFZ-DMF, SFZ-DMA and SFZ-NMP solvates respectively. 75x80mm (300 x 300 DPI)


Page 24 of 25

Page 25 of 25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 8. Relative contributions of the SFZ molecule to the Hirshfeld surface area for the various close intermolecular contacts. 70x38mm (300 x 300 DPI)


Insight into the Role of Hydrogen Bonding in the Molecular Self

Recommend Documents