Polymorphism, Intermolecular Interactions, and Spectroscopic Properties in Crystal Structures of Sulfonamides

Accepted Manuscript Polymorphism, Intermolecular Interactions, and spectroscopic properties in Crystal Structures of Sulfonamides C. Ignacio Sainz-Díaz, Misaela Francisco-Márquez, Catalina Soriano-Correa PII:

S0022-3549(17)30707-4

DOI:

10.1016/j.xphs.2017.10.015

Reference:

XPHS 963

To appear in:

Journal of Pharmaceutical Sciences

Received Date: 22 July 2017 Revised Date:

15 September 2017

Accepted Date: 2 October 2017

Please cite this article as: Sainz-Díaz CI, Francisco-Márquez M, Soriano-Correa C, Polymorphism, Intermolecular Interactions, and spectroscopic properties in Crystal Structures of Sulfonamides, Journal of Pharmaceutical Sciences (2017), doi: 10.1016/j.xphs.2017.10.015. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Polymorphism, Intermolecular Interactions, and spectroscopic properties in Crystal Structures of Sulfonamides

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C. Ignacio Sainz-Díaz1*, Misaela Francisco-Márquez2, Catalina Soriano-Correa3

IACT, CSIC-Universidad de Granada, Av. de las Palmeras, 4, 18100-Armilla, Granada, Spain. ([email protected])

Instituto Politécnico Nacional-UPIICSA. Té 950, Col. Granjas México, C.P. 08400 Mexico City, Mexico 3

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FES-Zaragoza, Universidad Nacional Autónoma de Mexico, Iztapalapa, C.P. 09230

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Mexico City, Mexico

ABSTRACT

The antibiotics family of sulfonamides has been used worldwide intensively in human

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therapeutics and farm livestock during decades. Intermolecular interactions of these sulfamides are important to understand their bioactivity and biodegradation. These interactions are also responsible for their supramolecular structures. The intermolecular

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interactions in the crystal polymorphs of the sulfonamides, sulfamethoxypyridazine and sulfamethoxydiazine, as models of sulfonamides, have been studied by using quantum

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mechanical calculations. Different conformations in the sulphonamide molecules have been detected in the crystal polymorphs. Several intermolecular patterns have been studied in order to understand the molecular packing behaviour in these antibiotics. Strong intermolecular hydrogen bonds and π-π interactions are the main driving forces for crystal packing in these sulfonamides. Different stability between polymorphs can explain the

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ACCEPTED MANUSCRIPT experimental behaviour of these crystal forms. The calculated infrared spectroscopy

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frequencies explain the main intermolecular interactions in these crystals.

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ACCEPTED MANUSCRIPT INTRODUCTION

A great family of antibiotics and one of the first synthetic antibiotics is the sulfamide

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group. Sulfamides have been used extensively worldwide for decades and are effective antimicrobial drugs for the prevention of infections in cattle, poultry, and swine (prophylaxis), to treat veterinary diseases, and to promote growth. More than millions of

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tons of antibiotics have been used worldwide and more than 20% correspond to sulfamides. 1 Nowadays, the main use of sulfamides is in veterinary for intensive livestock production.

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These antibiotics and metabolites are eliminated through animal excretions and hence they are persistent in the manure liquids. 2 As a result of the extensive use of sulfamides in the animal industry, residues of these drugs in food samples are a major concern because they contribute to the development of antibiotic resistant pathogenic bacteria. The presence of these antibiotics and their derivatives in environment can alter the bacterial resistance to

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animals and humans through the soil, water and food chains.3

One important sub-group of these antibiotics is the sulfonamides whose molecular

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structure has a sulfonic group joined to one amino group. The sulfone group can have joined

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an aromatic ring, like a 4-aminophenyl moiety, and the amino group can be monosubstituted by different groups. The sulfonamides, Sulfamethoxypyridazine S1 (4-amino-N-(6methoxypyridazin-3-yl)benzenesulfonamide) and Sulfamethoxydiazine S2 (sulphameter or sulfamethoxypirimidine, or 4-amino-N-(5-methoxy-2-pyrimidinyl)benzenesulfonamide) can be representative models of this drug family. These compounds are used widely in therapeutics and represent two groups of sulfonamides, sulfonamido-pyrimidines and sulfonamido-pyridazines. These molecules have similar structures with the same 3

ACCEPTED MANUSCRIPT substituents, a p-aminobenzenic moiety joined to the sulfoxy group and a methoxy group joined in a para position of the heterocycle ring with respect to the sulphonamide group. The relative disposition of N atoms in the heterocyclic ring is the only difference between

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these molecular structures (Fig. 1). The compound S2 is twice more active than S1 in the antibacterial bioactivity.4,5

Crystal polymorphism is becoming an interesting subject in pharmaceutical chemistry in

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last decades.6,7 One molecule can have different packing modes forming different

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polymorphs. Each polymorph can show different intermolecular interactions. Several polymorphs have been reported in sulfonamides.8 Polymorphism is present also in S1 and S2. The first crystallographic data of S1 were reported in 1981 by Lee9 and Rambaud et al.10 Both crystal structures are similar: Lee (P21/c, Z = 8, a = 8.70 Å, b = 11.08 Å, c = 26,64 Å, β = 100.5º), and Rambaud (P21/n, Z = 8, a = 8.72 Å, b = 11.31 Å, c = 26,90 Å, β =

reported. Basak et al.

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97.9º). Later Rambaud et al.11 reported two new polymorphs but no atomic coordinates were 12

reported a more refined structure of the same polymorph of S1

reported by Rambaud (P21/n, Z = 8, a = 8.72 Å, b = 11.29 Å, c = 26,87 Å, β = 98.0º).

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Haridas et al. reported a new polymorph of S1 with no atomic coordinates for H atoms (P c,

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Z = 8, a = 8.86 Å, b = 11.43 Å, c = 27.44 Å, β = 100.6º).13 On the other hand, S2 presents also several polymorphs: form i (C2/c, Z = 8, a = 13.37 Å, b = 11.74 Å, c = 15.93 Å, β = 97.9º);14 form ii (P21/c, Z = 4, a = 13.09 Å, b = 5.58 Å, c = 17.22 Å, β = 99.98º, no H atoms coordinates reported);15 form iii (P21/c, Z = 8, a = 8.36 Å, b = 26.83 Å, c = 11.96 Å, β = 111.36º);14 and form iv (P21/c, Z = 2, a = 8.57 Å, b = 5.64 Å, c = 12.98 Å, β = 99.6º, no atomic coordinates reported).16 These molecules adopt different conformations in their crystal polymorphs. Polymorphic transformations of S111 and S217,18 have been explored 4

ACCEPTED MANUSCRIPT previously with empirical thermodynamic calculations.19 Nevertheless, there is a lack of knowledge for understanding properties of these molecules, however no study at molecular

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level of these pharmaceutical drugs has been found.

One of the aims of this work is to explore the interatomic interactions in the crystal structure of polymorphs of these sulphonamides, S1 and S2, by means of molecular modeling calculations at quantum mechanical level. This kind of calculations has provided

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to be a useful tool for QSAR and drug design pharmaceutical studies,20 and polymorph

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predictions.21 Our calculations have confirmed that the crystal forms reported by Lee 9, Rambaud,10 and Basak12 correspond to the same polymorph. The main intermolecular interactions for the crystal packing of these sulfonamides are strong H bonds between sulfoxy O atoms and NH H atoms, and π-π interactions between aromatic rings. Infrared frequencies were calculated and show that these intermolecular interactions produce

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frequency shifts in these molecules.

COMPUTATIONAL METHODS

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Quantum mechanical calculations based on density functional theory (DFT) and

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Hartree-Fock methods have been performed for the organic molecules. The electronic structure has been calculated with a triple-ζ basis set with polarization functions for all atoms, augmented with diffuse functions using the hybrid functional BHandHLYP/6311+G**.

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The M06-2X functional with double amount of nonlocal exchange was also

used since it describes quite well intermolecular interactions, M06-2X/6-311+G**.24 All geometries were fully optimized at this level using the Berny analytical gradient method without any geometry constraint within the Gaussian-09 code-package.

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Normal mode 5

ACCEPTED MANUSCRIPT analyses have been performed to confirm the nature of the stationary points, finding only positive eigenvalues for minima. The harmonic vibration frequencies were calculated by means of finite atomic displacements and diagonalizing the mass-weighted second-

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derivative Hessian matrix.

Ab initio calculations of the periodic crystal models were performed using DFT methods based on plane-waves by means of the CASTEP code.26 Calculations were restricted to the Γ

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point in the irreducible wedge of the Brillouin zone. In all structures, all atoms were relaxed by means of conjugated gradient minimizations at constant volume. The local density

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approximation (LDA) with CA-PZ (Ceperley and Alder - Perdew and Zunger)27 parameterization of the exchange-correlation functional was used since previous works revealed that these conditions reproduce well intermolecular interactions.28 Ultrasoft pseudopotentials and an energy mesh cut-off of 300 eV were used.

In all cases the cohesion energy has been calculated in the usual way: Ecohesion = Ecrystal− z

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Emolecule, where Ecrystal is the energy of one unit cell of the crystal polymorph and z is the number of molecules that form the unit cell of the crystal lattice. The X-ray diffraction (XRD) patterns were simulated from the atomic positions of the crystal lattices studied by

MODELS

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using the Reflex module of the Materials Studio package. 29

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Crystal lattice structures of several polymorphs of sulfonamides were generated from the atomic positions reported in the crystallographic data of Sulfamethoxypyridazine (S1)10,12,13 and Sulfamethoxydiazine (S2)14,15. These data were taken from the Cambridge Structural Database (CSD). For S1, the polymorph reported by Rambaud et al.11 was not considered owing to the lack of atomic positions and the structure reported by Lee9 was considered to be similar to that reported by Rambaud10 in the same year. Then the S1 crystal forms studied were named S1-I (CSD refcode SLFNM06)12, S1-II (CSD refcode 6

ACCEPTED MANUSCRIPT SLFNM01)10, and S1-III (CSD refcode SLFNMF13)13. For S2, the polymorph reported by Bettinetti et al.16 was not considered due to the lack of atomic coordinates. Then the crystal forms studied for S2 were named maintaining the original nomenclature: S2-i (CSD refcode

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SAMPYM)14, S2-ii (CSD refcode SAMPYM03)15, and S2-iii (CSD refcode SAMPYM01)14. In the cases where the atomic coordinates of all or some H atoms were not reported, these H atoms were placed manually and after optimized. From these crystal forms, molecular

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structures and polymolecular clusters were extracted and 3-D periodical boundary conditions were applied. The crystal and molecular structures were analysed by using the Material

RESULTS AND DISCUSSION

Crystal structures

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Studio package.29

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The atomic positions of the crystal polymorphs of these sulfonamides were optimized at DFT/LDA level maintaining the experimental cell parameters. In S1, the crystal structure with lowest energy is S1-I that was optimized from the polymorph reported by Basak et al.12

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This structure is similar and has similar energy that S1-II optimized from the reported

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polymorph by Rambaud et al.10 This could indicate that both are apparently different refinements of the same structure (see later). The polymorph S1-III, optimized from that reported by Haridas et al.13, is 0.35 eV per molecule less stable than the former one (Table 1). This is consistent with the slightly higher density of S1-I than S1-III according with previous works in other organic crystals.19 This energy difference is due to the intermolecular interactions and conformations of the sulphonamide molecules. Several conformations of these molecules were defined in a 7

ACCEPTED MANUSCRIPT previous work.30 Using the heterocyclic N atoms as reference, those conformers with the methoxy group oriented to the same or opposite side of these N atoms are named conformers syn or anti, respectively. Those conformers with the SN-H bond oriented to the same or

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opposite side of these heterocyclic N atoms are named conformers cis or trans, respectively. Besides, considering the disposition of these heterocyclic N atoms in the left part of the heterocyclic ring viewed from methoxy group, the aromatic ring of the aniline moiety can be

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oriented in the up-side or in the down-side with respect to a horizontal disposition of the

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heterocyclic ring (Figures 1 and 2).

In both polymorphs, S1-I and S1-II, the conformations of sulfonamide molecules are syn-trans-up, syn-cis-up, syn-trans-down, and syn-cis-down. The unit cell is formed by 8 molecules, being two molecules in each conformation, where the conformers of type up are interacting with the up ones and the down conformers with the down ones (Figure 3). The

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disposition of the molecules along the crystal lattice is similar for both crystal forms, and the only difference is the displacement of atoms with respect to the origin of the crystallographic reference (Figures 3a and 3b). This indicates that these crystal forms are actually the same

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polymorph but obtained with a different refinement. On the other hand, in the S1-III

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polymorph four different conformers are present in the unit cell of the crystal structure: syncis-up, syn-trans-up, anti-cis-down, and anti-trans-down (Figure 3c).

The crystal form of S2 with lowest energy is S2-ii optimized from the polymorph

reported by Caira.15 This crystal form is 8.28 eV more stable than the most stable polymorph of its structural isomer S1. This energy difference is due to the molecular structure and the packing energy. The packing energy of S2 is 3.286 eV more negative than in S1. Then, the 8

ACCEPTED MANUSCRIPT crystal formation of the most stable polymorph of S2 is more exothermic than that of the most stable polymorph of S1. Besides, the S2 molecule is 0.62 eV (at DFT/LDA level) more stable than the most stable conformer of its structural isomer S1, being consistent with

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previous calculations at MP2/6-311G** level (0.55 eV).30 Taking into account that there are 8 molecules of sulfonamide per unit cell the energy difference is 4.99 eV per unit cell only owing to the molecular structure. Hence, the energy difference due to the molecular

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structure plus the packing energy will be 8.276 eV matching the energy difference between the most stable polymorphs of the crystal structures of both sulfonamides. This can indicate

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that the intermolecular interactions are similar in the most stable polymorph of each compound.

The polymorphs i and iii of S2 have 2.91 and 2.49 eV more energy than ii, respectively, due to the intermolecular interactions (Table 1). This is consistent with

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experimental kinetic studies where the transformation of ii to iii polymorphs was endothermic.17 Experimental studies found that all polymorphs are transformed to polymorph i heating at 150 ºC,18 indicating that this form i has higher energy according with

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our calculations. However, this form i changes to the polymorph iii during storage at room

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temperature according with our results where iii is more stable than i. This is also consistent with previous calculations based on empirical force fields.19

The relative energy of the conformers of these molecules was calculated by different

methods in our previous work.30 In S1 the most stable conformers are syn-cis-up and syncis-down and the conformers with highest energy are those of the anti group. These last conformers anti are present only in the S1-III polymorph. This can justify the higher energy 9

ACCEPTED MANUSCRIPT of S1-III with respect to S1-I. In all polymorphs of S2, the sulfonamide molecules are in the conformations syn-up and syn-down (Figure 4) that have similar energy.30 However the energy differences between polymorphs crystal lattices are higher than that due to the

structures should be due to intermolecular interactions.

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relative energy of conformers for S1 and S2. Hence the energy differences between crystal

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The XRD patterns of the experimental and optimized crystal structures were simulated and compared. The XRD patterns of the experimental structures of S1-I and S1-II show

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identical reflection positions with slight differences in the relative intensity of some reflections (Figure 5). The molecules arrangements of both crystal forms were superimposed finding a great coincidence (Figure 6). Hence, this confirms that both forms belong to the same polymorph and both were reported with different refinements. The profiles of the optimized structures in our DFT/LDA calculations show the same reflections that the

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experimental ones with only some differences in the relative intensities of some reflections, especially in S1-III and S2 polymorphs (Figures 5 and 7). This indicates a good validation of

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our calculation level for these structures.

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Intermolecular interactions

The main intermolecular interactions in S1 and S2 are similar for all polymorphs. The

most strong interactions are hydrogen bonds between sulfoxy O atoms and amino H atoms of aminophenyl ring, between sulfoxy O atoms and the H atom of SNH group, between the methoxy O atom with the amino H atoms, between the heterocyclic N atoms and the amino H atoms, and between the heterocyclic N atoms and one SNH H atom (Table 1). Hence, the sulfoxy and methoxy O atoms and the heterocyclic N atom act as H bond acceptors and the 10

ACCEPTED MANUSCRIPT SNH, and amino H atoms act as H bond donors. However, these interactions depend on the kind of conformer pairs. The H bond strength between the sulfoxy O atom and the amino H atom is similar for all polymorphs being slightly stronger in S1-I for S1 and S2-iii for S2.

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The H bond between the sulfoxy O atom and the HNS H atom is stronger than the former one, especially in S1-III. The heterocyclic N atom acts as a H bond acceptor forming a strong H bond with HNS H atom in S2-ii, being the strongest one in this crystal form. This

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H bond acceptor forms also a weaker H bond with one aromatic CH H atom with longer distance and smaller (donor..H..acceptor) angle, due to the low H-donor character of

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aromatic CH groups. The methoxy group acts as an H bond acceptor forming a H bond with the amino H atoms, and as a H bond donor forming a H bond with a sulfoxy O atom. This last one is weaker due to the low H-bond-donor character of the CH3 group of the methoxy moiety.

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Additional π-π interactions between the aromatic rings contribute to the crystal packing of these sulfonamides (figure 8). In S1-I the heterocyclic rings can be in a parallel orientation but rotated each other at a distance of 3.7–3.9 Å, whereas the aniline ring are

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quasi-perpendicular with a CH H atom oriented to the aromatic ring at 2.56 Å. A large

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network of parallel 2+2 heterocycles formed by four molecules was detected in the crystal lattice of S1-I (figure 8a). In this pattern the heterocyclic N atoms are in the opposite direction each other with two hydrogen bridges between the methoxy H atoms and the sulfoxy O atoms d(OCH…O=S) = 2.64-2.79 Å, maintaining the heterocycles at an average distance of 3.7 Å. Each heterocycle-pair is formed by intermolecular hydrogen bonds, d(S=O…HNS) = 1.673 Å, d(N=N…HNS) = 1.686 Å, and d(N=N…HC) = 2.134 Å. In S1III two intermolecular relative orientations are observed in the heterocycles: a ring-pair 11

ACCEPTED MANUSCRIPT forming an angle of 33º at an average distance of 3.634 Å, and a ring-pair almost parallel with an angle of 8º but displaced sideways with a d(N=N…C=C) = 3.176 Å. The aniline

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rings are almost perpendicular with an angle of 80º and a distance of 2.782 Å.

In S2-ii the aromatic aniline rings are parallel at 3.393 Å. These rings are in an opposite sense where the sulfoxy O atoms form H bonds with the amino H atoms with d(SO…HN) = 2.044 Å (figure 8b). This motif forms a cycle of 16 atoms with two donors

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and two acceptors named as a R22 (16) motif according to previous works.8 In S2-iii the

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aromatic aniline rings are quasi-parallel at 3.595 Å forming an angle of 22º between syn-up and syn-down conformers with hydrogen bonds between the sulfoxy O atoms and the aromatic H atoms d(SO…HC) = 2.417 Å (Figure 8c). In this polymorph the heterocyclic rings are parallel in the opposite direction at 3.8-4.0 Å between syn-up and syn-down conformers forming a R22 (20) motif with d(SO…HCO) = 2.577 Å (figure 8d). Similar

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motif is observed in S2-i where the heterocyclic rings are in a parallel orientation in the opposite direction with an average non-bonding distance of 3.291 Å between syn-up and syn-up conformers with hydrogen bonds between the sulfoxy O atoms and the methoxy H

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atoms d(SO…HCO) = 2.215 Å (figure 8e). In this polymorph the heterocyclic rings can also

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adopt a quasi-parallel orientation at a distance of 3.500 Å forming an angle of 20º between syn-down and syn-down conformers. Similar interactions between aromatic rings have been observed in crystal structures of other sulfonamides.31,32

These intermolecular H bonds can be combined forming characteristic patterns between molecules that can be considered as supramolecular synthons in S1 and S2 (Figures 9a-i). In S1-I a pattern, P1, is formed between syn-cis-up and syn-trans-up conformers where 12

ACCEPTED MANUSCRIPT three H bonds occurs consecutively forming a double ring of 7 and 8 members between two molecules (Figure 9a). The amino group of aniline ring shows a pattern P2 forming H bonds with two sulfoxy O atoms or with two different O atoms, a sulfoxy one and a methoxy one

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(Figure 9c). The sulfoxy O atoms can have H bonds with amino H atoms or with methoxy H atoms of different molecules forming a pattern P3. In this polymorph, a supramolecular network of hydrogen bonds was observed, pattern P8 (Figure 9i), that joins four molecules

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with one sulfoxy O atom as H bond acceptor and two amino and one HNS groups as H bond donors. In S1-III a P1 pattern is also formed between syn-cis-up and syn-trans-up

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conformers.

In S2-i the pattern P1 is also observed between syn-up and syn-down conformers in a similar way that in S1-I with the difference of the heterocyclic N atoms and each molecule acts as H donor alternatively, SNH…OS, heteroN…HNS, and heteroNCH…heteroN (Figure

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9b). In this polymorph, the pattern P2 is observed between the amino and sulfoxy groups forming weak H bonds in a cycle of 6 members where one H atom is shared with a methoxy O atom (Figure 9c). A pattern P3 connecting 3 molecules is also observed in S2-i with one

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sulfoxy O atom shared with two H atoms from different methoxy groups (Figure 9d). In S2-

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ii the pattern P4 is observed between syn-up and syn-down conformers with four H bonds forming a triple cycle of 7, 8 and 7 members where each molecule acts as H bond donor alternatively, SO…HC, SNH…NC, CN…SNH, and CH…OS (Figure 9e).

S2-iii shows a symmetric pattern P5 between syn-up and syn-down conformers forming a cycle of 8 members with two hydrogen bonds between the sulfoxy O atom and the SNH H atom, d(SO…HNS) = 1.668 Å in a R22 (8) motif (Figure 9f). The conformers syn13

ACCEPTED MANUSCRIPT down and syn-down of S2-iii show also another cycle of 8 members (pattern P6) with two hydrogen bonds formed by the aminobencenic amino H atoms with the sulfoxy O atom and the heterocyclic N atom, d(SO…HNH) = 2.546 Å and d(CN…HNH) = 2.139 Å. These

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groups, sulfoxy and heterocycle, can belong to different molecules forming the same pattern P6 connecting 3 molecules, syn-up, syn-down, syn-up, in this polymorph with d(SO…HNH) = 1.668 Å, and d(CN…HNH) = 2.271 Å. These aminobencenic amino H atoms form also

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hydrogen bonds with heterocyclic N atoms from different molecules, d(CN…HNH) = 2.139 and 2.271 Å, sharing one hydrogen bond with one sulfoxy O atom d(SO…HNH) = 2.546 Å

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(Figure 9g). Besides, in S2-iii the methoxy O atom can have electrostatic interactions with two aromatic H atoms, d(H3CO…HC) = 2.616, 2.809 Å. The methoxy O atoms can act as H bond acceptor with one aromatic H atom forming the pattern P7 (Figure 9h). In this polymorph sulfoxy O atoms accept hydrogen bonds from aromatic H atoms, d(SO…HC) =

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2.417 Å forming a cycle of 10 atoms with a R22 (10) motif.

In order to evaluate the contribution of these intermolecular interactions to the crystal formation, some dimers of these sulfonamides were generated and optimized at the

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BHandHLYP/6-311+G** and M06-2X/6-311+G** levels: S1D1 (a dimer between the S1

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conformers syn-trans-down and syn-cis-down), S1D2 (a dimer between the S1 conformers syn-trans-up and syn-cis-up), S1D3 (a dimer between the S1 conformers anti-cis-up and anti-cis-down), S2D1 (a dimer between the S2 conformers syn-up and syn-down), S2D2 (a dimer between the S2 conformers syn-down and syn-down), and S2D3 (a dimer between the S2 conformers syn-down and syn-up). Both calculation levels yielded similar geometries (Figure 10).

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ACCEPTED MANUSCRIPT In S1D1 and S1D2 the intermolecular interactions are mainly the H bonds SNH…O=S, NN…HNS, and NN…HC like the association pattern P1 described above. Both dimers show similar energy. The S1D3 dimer is less stable than the former S1 dimers (Table 2) and

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the main intermolecular interactions are two H bonds SNH…O=S (Figure 10) forming the pattern P5 (Figure 9). The same pattern P5 is found in S2D1. This last dimer is the most stable one of those studied for S2, being 1.396 eV more stable than the most stable one of

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S1. This last energy difference between the structural isomer S1 and S2 is consistent with previous calculations where the isolated molecule of S2 was more stable than S1. The dimer

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S2D2 shows the pattern P1 and S2D3 shows the pattern P4. S2D3 is more stable than S2D2 due to the additional S=O…HC hydrogen bond (Figure 10).

The energy differences between dimers are due to the packing energy and the relative energy between the conformers, which form the dimers. S1D3 has more energy due to its

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lower packing energy and the higher energy of the anti conformations of S1 in this dimer. In S2 the energy differences between conformers are not significant and the relative energy values are mainly owing to the packing energy (Table 2). On the other hand, no direct

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relationship between the relative energy values and the H bond distances was observed.

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Nevertheless, observing the geometry of these dimers, a certain relationship was observed between the number of H bonds per dimer and energy. The most stable one, S1D2, shows more H bonds than S1D3 (figure 10) and similarly S2D1 have more H bonds than S2D2. However, the packing energy of these dimers (Table 2) is much lower than that of the crystal forms (Table 1). Hence, additional intermolecular interactions to those observed in these dimers should be present in the crystal lattice: hydrogen bonds, π-π, and C-H/π interactions.

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ACCEPTED MANUSCRIPT The tendency of the relative energy differences between dimers is similar in all calculation levels compared. The relative energy values calculated at BHandHLYP/6-311+G** level are smaller than at M06-2X/6-311+G** level. The M06-2X functional describes better the weak

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intermolecular interactions existing in these dimers.24 Nevertheless, intermediate values are obtained with M06-2X/6-311++G(2d,2p) calculations on geometries obtained at M06-2X/6311+G** level (M06-2X/6-311++G(2d,2p)/M06-2X/6-311+G** level). Probably the

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inclusion of more diffuse and polarization functions in the basis sets used can describe better

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the intermolecular interactions.

No significant changes are observed in the energy differences between dimers calculated with the aqueous media simulation model, described through the SMD model33, except in S1D3 and S2D2 that show a lower energy excess. The water molecules can have better access to the intermolecular hydrogen bonds in these last dimers and stabilize them,

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especially in S2D2 one (figure 10). No relationship between the relative energy values and dipole moment of dimers was observed. Experimentally the polymorph S2-i changes with the time to the form S2-iii, according with our results where the S2-iii is more stable than

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S2-i. However, in presence of water the polymorph S2-iii is obtained. This could consider

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apparently that the dimer S2D3 would be more probable in a polar medium, like water, due to its higher dipole moment obtained in our calculations (Table 2). However, the association pattern P5 is more probable in S2-iii. This pattern exists also in S2D1 that is the most stable dimer, however this dimer has very low global dipole moment. Nevertheless, the association centre is very polar and water molecules can interact with the sulfoxy groups. Besides, S2-iii is the only one polymorph of S2 that has the association patterns P5, P6 and P7. This means thataqueous media favour the formation of these last patterns. Then, considering a non16

ACCEPTED MANUSCRIPT classical crystallization process a previous amorphous state34 could be formed in presence of water molecules. This amorphous proto-crystal allows the molecular mobility to adopt an ordered pattern and crystallize in a certain polymorph depending on the crystallization

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conditions (solvent and temperature). In the hypothetical amorphous proto S2-iii form, the presence of water would facilitate the formation of the P5, P6, and P7 association patterns. Our results yield to propose this hypothesis and further investigations will be performed

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following this way.

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Spectroscopical properties

Although no detailed experimental study of the assignments of infrared frequencies of our studied sulfonamides has been reported previously, the simplest molecule of these series can be considered, the sulphonamide, where the aminophenyl ring and the sulfonamide group can be compared with our studied molecules. Previous studies have been reported for

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sulfadiazine that is similar to S2 but without methoxy group.35 Comparing the experimental vibration modes of sulfadiazine, which are not significantly affected by intermolecular interactions and the presence of the methoxy group, with our calculated frequencies of the

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most stable conformer of S2, a linear relationship was observed with a scale factor of 0.944

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for comparisons with our values calculated at M06-2X/6-311G(d,p) level. This is consistent with previous general scale factor found for this calculation level. 36

The harmonic frequencies of the main vibration modes are described in Table 3 for the main conformers of S1. Slight frequency differences can be observed in the main vibration modes of conformers. The conformation syn/anti has not significant effect on the stretching ν(NH2) frequency. However the up conformers have lower ν(NH2) frequencies than the down ones, 17

ACCEPTED MANUSCRIPT and the cis conformers have higher ν(NH2) frequencies than the trans ones. This occurs for both asymmetric and symmetric modes of ν(NH2). In this mode the asymmetric vibration appears at higher frequency than the symmetric one. The ν(NH) mode of the SNH group

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appears at higher frequency in trans conformers than in cis ones, especially in the transdown conformers. Probably the interaction of this N-H bod with the dipole S=O is stronger in the trans conformers (Figure 1) shifting the ν(NH) frequency. The ν(CH) of the

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heterocycle appears at higher frequency in the cis-down conformers due to the stronger interaction of these C-H bonds with the π electron cloud of the aromatic ring (Figure 1). This

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difference is observed in both asymmetric and symmetric ν(CH) modes, where the asymmetric one appears at lower frequency than the symmetric one. The same difference was observed in the ν(CH) modes of the aromatic ring. In this mode two H atoms can be distinguished; those oriented to the same side (syn) or the opposite side (anti) to the SN-H

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group. In some conformers the symmetric ν(CH) mode appears at higher frequency in the aromatic CH bonds anti to SN-H than the syn one, due to a stronger interaction between the aromatic H bond and the heterocyclic N atom (Figure 1). On the other hand, the ν(CH) of

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methoxy group appears at higher frequency when the methoxy group is in syn orientation with respect to the heterocyclic N atoms than in anti one. The opposite frequency shift is

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observed in the symmetric umbrella bending δ(CH) and in the stretching ν(C-O) modes. These shifts can be explained due to the interactions of these vibrations with the heterocyclic N atoms.

In general no significant differences in frequency were observed between the conformers of S2 (Table 4). The ν(NH) modes of the amino group in S2 appear at similar frequencies 18

ACCEPTED MANUSCRIPT that those of S1 (Tables 3 and 4). The experimental values of solids of a sulfadiazine derivative

35

(without methoxy group) and sulphanilamide37 of ν(NH) modes of the amino

NH2 and SN-H groups appear at lower frequencies than the calculated ones, due to the

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intermolecular interactions with these H atoms in the crystal structure by H bonds as found above. Our calculations allow distinguishing the ν(CH) modes of the heterocyclic C-H bonds where those oriented to the same side (syn) to the methoxy group appear at higher

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frequency than those oriented to the opposite side (anti). In the aromatic ν(CH) vibrations the asymmetric and symmetric modes can be also distinguished in our calculations, where

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the symmetric ones appear at higher frequency than the asymmetric ones. Besides, the aromatic ν(CH) vibrations of the C-H bonds oriented to the same side (syn) to the SN-H group can be distinguished to those oriented to the opposite side (anti). The δ(NH2) calculated frequencies are lower than the experimental values due to the effect of the

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intermolecular interactions in the crystal lattice.

In order to evaluate the effect of the intermolecular interactions on the vibration

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frequencies in these molecules, the vibration modes of the dimers of S1 and S2 studied above were calculated (Table 5). A lower frequency shift was observed in the ν(NH) modes

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of amino groups in the S1D1, S1D2 and S1D3 dimers with respect to the S1 conformers. However this effect is much smaller than that observed experimentally, because in these dimers the interactions on these groups are not hydrogen bonds but π-π interactions between aromatic rings that are weaker than the hydrogen bonds (Figure 10). No effect was observed in the S2D1, S2D2, and S2D3 dimers because the amino groups are oriented outside to the intermolecular interactions and the amino groups have no intermolecular interactions.

19

ACCEPTED MANUSCRIPT This frequency shift is greater in the SN-H groups and similar to experimental one, because in these dimers the SN-H groups form intermolecular hydrogen bonds (Figure 10). When the SN-H group forms a hydrogen bond with the heterocyclic N atom the ν(NH)

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appears at lower frequency than that forming a hydrogen bond with the sulfoxy group, because the SN_H…N interaction is stronger, d(SNH…NN) = 1.948 Å than the SNH…O=S, d(SNH…O=S) = 2.012 Å. In S2 dimers this effect is greater because the main

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intermolecular interactions are the hydrogen bonds of these SN-H groups. In S2D1 both hydrogen bonds are similar, SN-H…NC, and both ν(NH) are coupled in symmetric and

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asymmetric modes for both monomers. In S2D2 also both hydrogen bonds are similar, SNH…O=S, and the ν(NH) vibrations of both molecules are coupled in symmetric and asymmetric modes. As seen in S1 dimers these hydrogen bonds are weaker than SN_H…NC and the frequency shift effect is smaller than in S2D1. In S2D3 the same frequency shift

are different (Figure 10).

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occurs as in previous S2 dimers but no coupling was observed because the hydrogen bonds

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The asymmetric mode of the stretching ν(S=O) vibration of the dimers shows a frequency shift to lower values respect to the free molecules except in the S1D1 one. This

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fact is due to the intermolecular hydrogen bonds with NH H atoms, that are not present in S1D1.

CONCLUSIONS

20

ACCEPTED MANUSCRIPT In this work, quantum mechanical calculations have shown to be a useful tool to explore crystallographic studies on polymorphism of pharmaceutical drugs and the intermolecular interactions in the packing process forming the crystal lattices. Our calculations confirm that

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the crystal forms reported by Lee9 (CSD refcode SLFNM02), Rambaud (CSD refcode SLFNM01)10, and Basak (CSD refcode SLFNM06)12 are the same polymorph of S1. The most sable polymorph of S1 is the S1-I one and the most stable polymorph of S2 is the S2-ii

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one.

Different conformers are associated within the crystal lattice of these polymorphs.

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However, similar association patterns are observed between molecules. The main intermolecular interactions in the crystal structures of these sulfonamides are hydrogen bonds where the sulfoxy O atoms and the heterocyclic N atoms are the main H bond acceptors, and the amino groups are the main H bond donors. The π-π interactions are also important between the aromatic rings along with additional electrostatic interactions

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between some functional groups. All these intermolecular interactions are responsible of the crystal packing in the polymorphs of these sulfonamides. The relative energies between crystal forms are consistent with the experimental behavior of the transformations between

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polymorphs of these sulfonamides.

The frequencies of the main vibration modes obtained by means of high level calculations are consistent with experimental values of similar sulfonamides and have allow assigning bands to specific vibration modes that can be useful for interpreting experimental spectra of these drugs. The frequency variations in the vibration modes between different conformers indicate the intramolecular interaction between functional groups of the molecule. The calculation of frequencies of the dimers of S1 and S2 have allow understanding the 21

ACCEPTED MANUSCRIPT differences in infrared spectra of crystalline solids and isolated molecules of these sulfonamides, explaining the frequency shifts due to intermolecular interactions. These results will be useful for experimental studies of dissolution and nucleation of these

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sulfonamides by using infrared spectroscopy.

The results of our calculations allow explain the formation of polymorphs of these

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sulfonamides and open new hypothesis related with the crystallization mechanism for further investigations. This collaborative study of quantum mechanical calculations and

ACKNOWLEDGEMENTS

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crystallography can be a useful tool to explore other organic crystals.

Authors are thankful to A. Hernández-Laguna for the help in computing facilities, to the Andalusian Government projects (IAC09-I-4963, RNM1897 and RNM363) and the

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MINECO project (FIS2013-48444-C2-2-P) with FEDER funds for the financial support, to the Supercomputational Center of the Granada University (UGRGRID), to the Centro Técnico de Informática del CSIC, to the Mexican agency CONACYT for a grant, and to the

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Dirección General de Cómputo y de Tecnologías de Información y Comunicación (DGTIC)

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of the Universidad Nacional Autónoma de México (UNAM) for allocation of computer time on the Miztli supercomputer.

REFERENCES

1

Sukul, P.; Spiteller, M. Sulfonamides in the Environment as Veterinary Drugs. Rev. Environ. Contam. Toxicol. 2006, 187, 67–101. 2 Wehrhan, A.; Kasteel, R.; Smunek, J.; Groeneweg, J.; Vereecken, H. Transport of sulfadiazine in soil columns-Experiments and modelling approaches. J. Contaminant Hydrol. 2007, 89, 107-135.

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Wang, Z. H.; Zhang, S. X.; Nesterenko, I. S.; Eremin, S. A.; Shen, J. Z. Monoclonal Antibody-Based Fluorescence Polarization Immunoassay for Sulfamethoxypyridazine and Sulfachloropyridazine. J. Agric. Food Chem. 2007, 55, 6871-6878. 4 Wolff, M. E. Burger’s Medicinal Chemistry, Part II. 4th ed.; Wiley & Sons: New York, Vol. 2, Chapter 13, pp 1-40, 1979. 5 Mengelers, M. J. B.; Hougee, P. E.; Janssen, L. H. M.; Van Miert A. S. J. P. A. M. Structure-activity relationships between antibacterial activities and physicochemical properties of sulfonamides J. Vet. Pharmacol. Therap. 1997, 20, 276-283. 6 Cruz-Cabeza, A. J.; Bernstein, J. Conformational Polymorphism. Chem. Rev. 2014, 114, 2170-2191. 7 Martín-Islán, A. P.; Cruzado, M. C.; Asensio, R.; Sainz-Díaz, C. I. Crystalline Polymorphism and Molecular Structure of Sodium Pravastatin. J. Phys. Chem. B, 2006, 110, 26148–26159. 8 Adsmond, D. A.; Frant, D. J. W. Hydrogen bonding in sulfonamides. J. Pharm. Sci. 2001, 90, 2058-2077. 9 Lee, Y. J., Park, Y. J. The crystal and molecular structures of Sulfamethoxypyridazine. J. Korean Chem. Soc. 25, 219-227. 10 Rambaud, J.; Roques, R.; Declercq, J. P.; Germain, G.; Sabon, F. Structure crystalline et moleculaire du [ methoxy-6-pyridazyl-(3)]-sulfanilamide (sulfamethoxypyridazine). Bull. Soc. Chim. Fr. 1981, 153-160. 11 Rambaud, J.; Maury, L.; Pauvert, B.; Lasserre, Y.; Berge, G.; Audran, M.; Declercq, J. P. Etude comparative des trois formes polymorphes du N-(methoxy-6 pyridazyl-3)-sulfanilamide ou sulfamethoxypyridazine. I1 Farmaco 1985, 40, 152-164. 12 Basak, A. K.; Mazumdar, S. K.; Chaudhuri, S. Structure of N'-(6-Methoxy-3-pyridazinyl)sulfanilamide (Sulfamethoxypyridazine) Acta Cryst. C. 1987, 43, 735-738. 13 Haridas, M., Singh, T. P. Crystal and molecular structure of sulfamethoxypyridazine. Indian J. Chem., Sect. A: Inorg., Bio-inorg., Phys., Theor. Anal. Chem. 1986, 25, 707-713. 14 Guiseppetti, G., Tadini, C., Bettinetti, G.P., Giordano, F. 2-Sulfanilamido-5-methoxypyrimidine. Cryst. Struct. Commun. 1977, 6, 263-264. 15 Caira, M.R. Crystal structure of 5-Methoxysulfadiazine. J. Chem. Cryst. 1994, 24, 695. 16 Bettinetti, G. P.; Giordano, F.; La Manna, A.; Giuseppetti, G. Crystal structure of 2-Sulfanilamido-5methoxypyrimidine. Farmaco, Ed. Prat. 1974, 29, 493. 17 Moustafa, M.; Ebian, A. R.; Khalil, S. A.;Motawi, M. M. Sulfamethoxydiazine crystal forms. J. Pharm. Pharmacol. 1971, 23, 868-874. 18 Moustafa, M.; Ebian, A. R.; Khalil, S. A.; Motawi, M. M. Kinetics of interconversion of sulphamethoxydiazine crystal forms. J. Pharm. Pharmacol. 1972, 24, 921-926. 19 Gavezzotti, A.; Filippini, G. Polymorphic forms of organic crystals at room conditions: thermodynamics and structural implications. J. Am. Chem. Soc. 1995, 117, 12299-12305. 20 Smeyers, Y. G.; Bouniam, L.; Smeyers, N. J.; Ezzamarty, A.; Hernandez-Laguna, A.; Sainz-Diaz, C. I. Quantum mechanical and QSAR study of some α-arylpropionic acids as anti-inflammatory agents. Eur. J. Med. Chem. 1998, 33, 103-112. 21 Martín-Islán, A.P.; Martín-Ramos, D.; Sainz-Díaz, C. I. Crystal structure of minoxidil at low temperature and polymorph prediction. J. Pharm. Sci. 2008, 97, 815-830. 22 Becke, A. D. A new mixing of Hartree–Fock and local density functional theories. J. Chem. Phys. 1993, 98, 1372. 23 Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Frisch, M. J.; Frisch, A. GAUSSIAN 98 User’s Reference; Gaussian Inc.: Pittsburgh, PA, 1998. 24 Zhao, Y.; Truhlar, D. G. The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor. Chem. Accounts 2008, 120, 215–241. 25 Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Chesseman, J. R.; Zarzewki, V. G.; Montgomery, J. A.; Stratmann, R. E.; Burant, J. C. et al. Gaussian 03 (RevisionA.1), Gaussian, Inc., Pittsburgh, PA, 2004.

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Clark, S. J.; Segall, M. D.; Pickard, C. J.; Hasnip, P.J., Probert, M.J., Refson, K., Payne, M.C. First principles methods using CASTEP. Zeits. Kristal. 2005, 220, 567-570. 27 Ceperley, D. M.; Alder, B. J. (1980) Ground State of the Electron Gas by a Stochastic Method, Phys. Rev. Lett., 45, 566-569. 28 Ortmann, F.; Preuss, M.; Oetzel, B.; Hannewald, K.; Bechstedt, F. Charge Transport through Guanine Crystals. In High Performance Computing in Science and Engineering, Garching/Munich, Eds. Wagner, S; Steinmetz, M; Bode, A.; Brehm, M. 2007, Part VIII, 687-695. 29 Accelrys Software inc., Materials Studio Release Notes, Release 5.0, San Diego: Accelrys Software Inc., 2009. 30 Francisco-Márquez, M.; Soriano-Correa, C.; Sainz-Díaz, C. I. Adsorption of sulfonamides on phyllosilicate surfaces by molecular modeling calculations. J. Phys. Chem. C 2017, 121, 2905-2914. 31

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Tahir, M. N.; Shafiq, Z.; Shad, H. A.; Rehman, Z.; Karim, A.; Naseer, M. M. Polymorphism in a sulfamethoxazole derivative: coexistence of five polymorphs in methanol at room temperature. Cryst. Growth Des. 2015, 15, 4750-4755. 32 Yang, S. S.; Guillory, J. K. Polymorphism in sulfonamides. J. Pharm. Sci. 1972, 61, 26-40. 33 Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Universal solvation model based on solute electron density and on a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions. J. Phys. Chem. B 2009, 113, 6378-6396. 34 Cartwright, J. H. E.; Checa, A. G.; Gale, J. D.; Gebauer, D.; Sainz-Díaz, C. I. Calcium Carbonate Polyamorphism and Its Role in Biomineralization: How Many Amorphous Calcium Carbonates Are There? Angew. Chem. Int. Ed. 2012, 51, 2-13. 35 Ogruc-Ildriz, G., Akyuz, S., Ozel, A.E. Experimental, ab initio and density functional theory studies on sulfadiazine. J. Mol. Struct. 2009, 924-926, 514-522. 36 Alecu, I.M.; Zheng, J.; Zhao, Y.; Truhlar, D.G. Computational Thermochemistry: Scale Factor Databases and Scale Factors for Vibrational Frequencies Obtained from Electronic Model Chemistries. J. Chem. Theory Comput. 2010, 6, 2872–2887. 37 Varghese, H.T.; Panicker, C.Y.; Philip, D. Vibrational spectroscopic studies and ab initio calculations of sulfanilamide. Spectrochim. Acta A 2006, 65, 155–158.

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Captions of Figures Figure 1. Main conformers in S1. a) syn-cis-up, b) syn-cis-down, c) syn-trans-up, d) syntrans-down, e) anti-cis-up, f) anti-cis-down, g) anti-trans-up, and h) anti-trans-down.

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Figure 2. Main conformers in S2. a) syn-up, b) syn-down, c) anti-up, and d) anti-down.

Figure 3. Crystal structures optimized of the polymorphs of the sulphonamide S1, S1-I (a), S1-II (b), and S1-III (c). H, C, N, O, and S atoms are represented in white, gray, blue, red,

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and yellow colours. This color assignment is extended to the rest of figures. Figure 4. Crystal structures optimized of the polymorphs of the sulphonamide S2, S2-i (a), S2-ii (b), and S2-iii (c).

Figure 5. Powder XRD patterns of the crystal structures of S1 polymorph simulated from

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the optimized (a) and experimental (b) structures of S1-I; from the optimized (c) and experimental (d) one of S1-II, and from the optimized (e) and experimental (f) one of S1III.

Figure 6. Molecular arrangements superimposed of the S1-I and S1-II crystal forms.

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Figure 7. Powder XRD patterns of S2 polymorphs simulated from the optimized (a) and experimental (b) crystal structures of S2-i, from the optimized (c) and experimental (d) one of S2-ii; and from the optimized (e) and experimental (f) one of S2-iii. Figure 8. Interactions of π-π type between aromatic rings found in the crystal forms of S1 and S2. Distances are in Å. Models a1 and a2 correspond to different views of the same network.

Figure 9. Intermolecular association patterns observed in the crystal forms of S1 and S2; pattern P1 in S1 (a), P1 in S2 (b), P2 (c), P3 (d), P4 (e), P5 (f), P6 (g), P7 (h), and P8 (i). Distances are in Å.

25

ACCEPTED MANUSCRIPT Figure 10. Optimized structures of dimers of sulfonamides, S1D1 (a), S1D2 (b), S1D3 (c), S2D1 (d), S2D2 (e), and S2D3 (f). The main non-bonding interactions are highlighted with

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dashed lines.

26

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parameter

S1-Ia

S1-IIb

S1-IIIc

S2-ii d

S2-i e

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Table 1. Relative energy (eV per unit cell) and main intermolecular distances (in Å) of the optimized (at DFT/LDA level) crystal polymorphs S1 and S2. S2-iii f

Lattice energyg

0.0 (8.278)

Packing Eh

-63.880

SO…H2N

1.971-2.245

2.155-2.278

1.939-2.878

SO…HNS

1.673-1.681

1.686

1.616

heteroN…HNS 1.686

1.683

1.743

1.623

1.732-1.752

2.139-2.271

heteroN…HC

2.131

2.120

2.268-2.397

2.254

2.368-2.385

3.145, 2.139-2.271i

H3CO…HC

2.567

H3CO…H2N

2.066

SO…H3CO

2.331-2.667

2.827

0.0

2.910

2.487

2.404-2.928

1.668-2.546

1.686-1.696

1.668

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1.858

2.616-2.809

1.871

2.567

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2.079

2.043

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-67.166

2.245-2.599

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Starting from the experimental data of the S1 polymorph reported by Basak et al.12 b Starting from the structure reported by Rambaud et al.10 c Starting from the structure reported by Haridas et al.13 d Starting from the structure of polymorph ii of S2 reported by Caira considering 8 molecules per unit cell, Z=8.15 e Starting from the structure of polymorph i of S2 reported by Guiseppetti et al.14 f Starting from the polymorph iii of S2 from Guiseppetti et al.Error! Bookmark not defined. g Relative energy with respect to the most stable one; values in parenthesis are with respect to the lowest energy polymorph of S2. h Energy difference between crystal lattice unit cell and Z times the molecule energy. i HeteroN…H2N.

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a

0.167

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Table 2. Relative energy (in eV) and main intermolecular interactions (in Å) of sulfonamide dimers.a S1D1 S1D2 S1D3 S2D1 S2D2 S2D3 b b b 0.032, 0.012 0.0 0.544, 0.451 0.0 0.324, 0.267b 0.411, 0.334 (0.001) (1.396)c (0.484) (0.275) (0.252) 0.035 0.0 0.598 0.0 0.509 0.346 ∆G d 0.040 0.0 0.206 0.0 0.208 0.283 ∆E d 0.059 0.0 0.273 0.0 0.218 0.318 ∆G e 1.018 0.990 0.828 0.835 0.515 0.541 Pack. E µ (D) 11.84 13.0 9.03 0.82 3.82 12.49 SNH…OS 2.012 1.927 1.867 1.858, 1.863 1.875 CN…HNS 1.948 1.894 2.057 1.874 1.892 f CN…HC 2.713 2.660 2.553, 2.898 2.325 2.45 ring-ring 3.468 3.350 3.269 a Calculated at the M06-2X/6-311+G** level, energy values in parenthesis are from BHandHLYP/6-311+G** calculations. Energy is relative to

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Dimers Energy

the most stable structure and corrected with the zero point energy. b Calculated at M06-2X/6-311++G(2d,2p)/M06-2X/6-311+G** level. energy with respect to the most stable dimer of S2.

d

c

Total

Calculations including the solvent effect of water described through the SMD model.

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Packing energy with respect to the isolated molecules. f S=O…HC distance.

e

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Table 3. Calculated (at M06-2X/6-311+G** level) frequencies (in cm-1) of the main vibrational modes of IR of the main conformers of S1.

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S1 syn-cis-up S1 syn-cis-down S1 syn-trans-down S1 anti-cis-down S1anti-trans-down S1anti-trans-up 3520 3524 3515 3525 3519 3517 3417 3420 3413 3421 3416 3415 3356 3350 3416 3347 3418 3405 3045 3058 3039 3065 3043 3054 3027 3040 3009 3046 3027 3017 3031 3029 3050 3025 3028 3027 3024 3032 3041 3027 3046 3044 3015 3015 3006 3007 3011 3006 3006 3012 3025 3006 3008 3003 3000 3002 3010 3010 2992 2996 2972 2982 2966 2932 2927 2936 2896 2906 2894 2868 2862 2871 1563 1565 1565 1563 1562 1563 1588-1445 1591-1440 1597-1443 1588-1460 1588-1461 1588-1462 1399-1144 1401-1178 1401-1169 1397-1128 1400-1131 1399-1128 1425, 1409 1430, 1409 1425, 1409 1435, 1431 1434, 1425 1435, 1428 δ(CH) OCH3 1391 1388 1382 1394 1397 1399 δ(CH)umbrella OCH3 1300as, 1109, 1301as, 1309as 1324as, 1313as, 1108, 1309as, 1108, ν(SO)s 1057 1108, 1054 1104, 1053 1109, 1054 1053 1053 1123 1121 1117 1118 1118 1120 δ(CH) OCH3 1026 1027 1028 1060 1067 1065 ν(C-O) a Aromatic C_H bonds placed in the same side (syn) or opposite side (anti) with respect to the heterocyclic SN-H bond.

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Vibration mode ν(NH2)as ν(NH2)s ν(SN-H) ν(CH)s hetero ν(CH)as hetero ν(CH)s ar- syna ν(CH)s ar-antia ν(CH)as ar-syna ν(CH)as ar-antia ν(CH)as OCH3 ν(CH)as OCH3 ν(CH)s OCH3 δ(NH2)s δ(CH)+ ν(CC)rings+ δ(NH)

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Table 4. Calculated (at M06-2X/6-311+G** level) frequencies (in cm-1) of the main vibrational modes of IR of the main conformers of S2.

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Vibration mode syn-up syn-down anti-down experimental 3516 3514 3518 3423d, 3478e ν(NH2)as 3414 3412 3415 3355d, 3375e ν(NH2)s 3409 3409 3410 3259d ν(NH) 3032a, 3016b 3031a, 3016b 3027a, 3017b 3075d, 3031d ν(CH)as hetero 3044 3045 3045 3102d, 3086-3050e ν(CH)s ar- sync 3060 3058 3058 3066d ν(CH)s ar-antic 3026 3024 3025 3039d ν(CH)as ar-sync 3023 3023 3024 ν(CH)as ar-antic 3005 3006 3005 ν(CH)as OCH3 2935 2934 2933 ν(CH)as OCH3 2873 2872 2871 ν(CH)s OCH3 1563 1564 1562 1652d, 1629e δ(NH2)s 1595-1438 1595-1431 1596-1437 1594-1187d δ(CH)+ 1397-1139 1396-1137 ν(CC)rings+ δ(NH) 1396-1142 1430, 1424 1423 1431, 1424 δ(CH) OCH3 1403 1403 1403 δ(CH)umbrella OCH3 1292as, 1102 1101 1286as, 1101 1326asd, 1157d, 1313ase, 1147d ν(SO)s 1119 1119 1120 δ(CH) OCH3 1049 1049 1048 ν(C-O) a C-H bond oriented to the same side (syn) with respect to methoxy. b C-H bond oriented to the opposite side (anti) respect to methoxy. c Syn or anti orientation with respect to the heterocyclic SN-H bond. d Experimental data of sulfadiazine in KBr 35. e Experimental data of sulfanylamide in KBr 37.

ACCEPTED MANUSCRIPT Table 5. Calculated (at M06-2X/6-311+G** level) frequencies (in cm-1) of the main vibrational modes of IR of the dimers of S1 and S2.

ν(CH)as hetero

3075c, 3045d, 3020b

ν(CH)arortoSO-syne ν(CH)arortoSO_antie ν(CH)armetaSO-syne ν(CH)armetaSO-antie ν(CH)arortoSO ν(CH)ar

3048a, 3046b 3035b, 3031a 3013a, 3011b 3004a, 3000b

ν(NH2)s ν(NH) ν(CH)s hetero

δ(NH2)s

δ(NH)b δ(CH)+ ν(CC)rings+ δ(NH) δ(CH) OCH3

3031a

3025a, 3042b 3006

3057a,b

3041a

3007

3007a, 3008b

3025

3006

3006a, 3010b

3419a, 3417b

3011asa+b 2974sa+b 3034h

3200asa+b 3183sa+b

3015i

3015a,b,i, 3013b,h, 3011a,h

3009b

TE D 3010a, 2998b 2970b, 2966a 2896b, 2893a 1571a, 1563b 1448 16001452 14001142 1426a, 1425b, 1411b, 1410a

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ν(CH)s OCH3

3025

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ν(CH)as ar-syn

ν(CH)as OCH3

3037b

3037a, 3031b 3020a, 3005b 2993b

ν(CH)as ar-anti

ν(CH)as OCH3

3055a

3008a

S2D2 3521a, 3519b

S2D3 3513a, 3525b 3413a, 3422b 3243a, 2994b

3022a,h 3013a,i, 3007b,h, 3000b,i

3041sb,3040asb

ν(CH)s ar-anti

ν(CH)s ar-syn

S2D1 3515a, 3516b 3413a+b

3039a, 3032b

S1D3 3500a, 3478b 3399a, 3383b 3144a, 3211b 3068a, 3058b 3048a, 3038b

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S1D2 3499a, 3480b 3396a, 3387b 3229a, 3068b,g 3049b

SC

S1D1 3474a, 3477b 3385b, 3381a 3254a, 3132b 3034b

M AN U

Mode ν(NH2)as

3006a, 2999b 2968a, 2973b 2892a, 2897b 1566asa,b, 1562sa,b 1460 16011463 13851271 1429a, 1427b, 1410b

3001a

3023a+b

3007a

3024a+b

3018a, 3013b 2996a, 2994b 2930a, 2942b 2865a, 2875b 1567a+b

3044a+b

15921443 12681128 1433a, 1425b

3044sa, 3042asa, 3041asb 3019b, 3010a+b 3023a, 3015b 3034b

3005sa+b 3004asa+b 2940a+b

2992a, 2988b 2924a, 2926b

2876a+b

2861a,b

1563a+b

1565b

15971433 13971171 1430a+b, 1424a+b

1601-1437

1429a, 1424a 1431b,, 1425b

2996a, 2992b 2926a, 2930b 2863a, 2865b 1563

16051450 14241306 1431a, 1433b, 1425a, 1427b

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ν(SO)s

δ(CH) OCH3 ν(C-O)

(1418, 1386)a,f, 1387b 1312asa, 1307as b, 1274b 1274asb, 1110a, 1103b 1122 1029a, 1027b

(1416, 1385)a,f, 1387b 1268asb, 1110a, 1098b

(1410a, 1399b),f

1422a+b,f, 1400a+b

1413s a+b,f, 1407as a+b,f

(1297a, 1273b)as, 1113a, 1106b

1268asa+b, 1263asa+b 1047a+b

1271asa+b, 1269asa+b 1104a , 1098b

1304asa, 1277asb, 1110a, 1104b

1124a, 1120b 1028a, 1026b

1121a, 1116b 1057a, 1059b

1141, 1118 1045

1115a, 1119b

1119a, 1142b 1054a, 1052b

1054

Monomer A of the dimer. b Monomer B. c In orto position of the heterocycle with respect to the NHS substituent d In meta position with respect to the NHS subtituent. e syn and anti with respect to the NHS substituent. f Coupled with δ(NH). g Coupled with ν(CH) ar-ortoSO_anti of monomer A, 3069as and 3068s. h Syn with respect to the methoxy group. i Orientation anti with respect to the methoxy group.

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