Furosemide Cocrystals with Pyridines: An Interesting Case of Color

DOI: 10.1021/acs.cgd.5b01240. Publication Date (Web): October 27, 2015 ... Munshi , and Rajesh G. Gonnade. Crystal Growth & Design 2017 17 (6), 3071-3...
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Furosemide Cocrystals with Pyridines: An Interesting Case of Colour Cocrystal Polymorphism Ekta Sangtani, Sanjay Kumar Sahu, Shridhar H Thorat, Rupesh L. Gawade, Kunal K. Jha, Parthapratim Munshi, and Rajesh Ghanshyam Gonnade Cryst. Growth Des., Just Accepted Manuscript • Publication Date (Web): 27 Oct 2015 Downloaded from http://pubs.acs.org on October 27, 2015

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Furosemide Cocrystals with Pyridines: An Interesting Case of Colour Cocrystal Polymorphism Ekta Sangtani,a Sanjay K. Sahu, a Shridhar H. Thorat,a Rupesh L. Gawade,a Kunal K. Jha, b Parthapratim Munshi,b and Rajesh G. Gonnade* a a

Centre for Materials Characterisation, CSIR-National Chemical Laboratory, Dr. Homi Bhabha

Road, Pune 411 008, India. b

Department of Chemistry, School of Natural Sciences, Shiv Nadar University, Tehsil Dadri, UP

201314, India. KEYWORDS: Cocrystal, Colour Polymorphism, Conformation, Morphotrophism, Phase Transition, Stacking Interactions.

ABSTRACT: Furosemide (FS), a loop diuretic drug commonly used for the treatment of hypertension and edema exhibited colour cocrystal polymorphism with coformer 4, 4’-bipyridine (4BPY) in the stoichiometry 2:1 albeit both the API and the cocrystal former are colourless. Crystallization from ethanol, isopropanol, ethanol-water (v/v, 1/1) mixture, acetonitrile yielded pale yellow (form 1I, thin needles) and orange (form 1II, blocks) cocrystals concomitantly. Needles appeared from solution within a day; while the blocks were obtained after 1-2 days from the same flask indicating that yellow needles were formed faster, and the orange blocks were perhaps formed under thermodynamic conditions. Form 1I cocrystals could also be produced

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from the variety of common solvents. Cocrystallization of FS with 2, 2’ bipyridine (2BPY) and 4-amino pyridine (4AP) gave colorless cocrystals 2 and 3 respectively and did not exhibit polymorphism. The single crystal X-ray structures, powder X-ray diffraction, photophysical characterization, differential scanning calorimetry (DSC), hot stage microscopy (HSM) studies and density functional theory (DFT) calculations provide insight into the structure-property relationship. The common structural features observed in all the structures is the formation of sandwich motifs comprising FS and pyridines through π-stacking interactions. These motifs are linked differently through hydrogen bonding interactions in all the three directions. The significant colour difference between the two cocrystals dimorphs could be attributed to the different π-stacking patterns and hydrogen bonding interactions between molecules of FS and 4BPY in their cocrystal structures. Investigation on the origin of the colour difference using DFT calculations revealed the decrease in HOMO-LUMO gap for the form 1II cocrystals (orange) compared to form 1I crystals (light yellow). The crystal-to-crystal thermal transformation of forms 1I crystals to form 1II crystals of 1 suggests the role of π-stacking assemblies in driving the self-assembly.

Introduction. Development of multicomponent crystals or cocrystals1-5 of active pharmaceutical ingredients (API) evolved into a contemporary area of research firstly due to their involvement in enhancing physicochemical properties such as solubility, dissolution rate, bioavailability, stability, hygroscopicity, compressibility etc. without altering their therapeutic effect than is offered by conventional free API and secondly academic interests in molecular recognition driven assembly process.6-7 Constant and consistent effort to develop API cocrystals with suitable cocrystal

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former offers a much wider range of solid forms by which the physicochemical properties of a drug can be optimized or tailored that could be economically advantageous and intellectually inspiring.8-10 Reports on pharmaceutical cocrystals exhibiting polymorphism, an ability of a cocrystal to exist in two or more crystalline forms comprising same stoichiometry of the components, with different arrangements and /or conformations of the molecules in the crystal lattice are very less in numbers as compared to the polymorphs of the single component system. Lammerer et al.11 have shown that the compounds that are more prone to exhibit polymorphism can reveal polymorphism in cocrystals too as well as they are more likely to form cocrystals.12 Recent highlight by Aitipamula et al.13 revealed that 114 cocrystals exhibiting either packing or conformational polymorphism out of which only 17 were formed concomitantly. Furosemide (FS) is a loop diuretic drug 16-17 commonly used for the treatment of hypertension and edema arising from cardiac, renal, and hepatic failure. However, the drug belongs to class IV according to the BCS (Biopharmaceutics Classification System)

18

and suffers from both low

permeability and poor aqueous solubility. Nangia et al. reports three polymorphic forms of this drug, 19 of which one is thermodynamically stable (form 1) and other two forms (forms 2 and 3) are metastable, although the energy difference between them is very small. However, the thermal stability of form 1 crystals was attributed to the more efficient crystal packing and higher crystal density as compared to other two metastable forms. Different orientations adopted by conformationally flexible groups, sulfonamide and furan in the crystal structure is found to be the main cause of conformational polymorphism exhibited by FS. The polymorphic behaviour of FS was restricted in several of its cocrystals with cocrystal formers that locked the flexible group conformations. Currently there are several reported cocrystals of furosemide (FS) with coformers p-aminobenzoic

acid,

acetamide,

isonicotinamide,

caffeine,

urea,

adenine,

cytosine,

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pentoxifylline, Na and K salts which has been prepared to improve the dissolution rate of FS 20-24 and none of these cocrystals exhibit polymorphism.

However, cocrystals of FS with

nicotinamide produced five polymorphic cocrystals including one hydrated form. Crystal structures of all these polymorphs solved using laboratory powder X-ray diffraction21 revealed different conformation of FS molecule as well as that of conformationally rigid nicotinamide. This suggests that FS has ability to show conformational tuning even in cocrystals which eventually manifested into cocrystal polymorphism. In a quest to further investigate conformation polymorphs of FS in cocrystals we carried out its cocrystallization with 4, 4’bipyridine (4BPY), 2, 2’-bipyridine (2BPY) and 4-aminobenzoic acid (4AP). We chose bipyridines as cocrystal former (CCF) because 4BPY is the most frequently used coformer25 in the cocrystal synthesis and its cocrystals have great potential to exhibit polymorphism.13 Crystal structures of the cocrystal of FS with 4BPY and its solvates were reported.26 Interestingly, our investigation into the cocrystallization of FS and coformers 4BPY resulted in the formation of colour cocrystal polymorphs, form 1I (light yellow) and form 1II (orange) concomitantly in the stoichiometry 2:1 form 1I cocrystals underwent crystal-to-crystal thermal phase transitions to form 1II cocrystals. To the best of our knowledge, this is the first instance of colour cocrystal polymorphism in which the individual components are colourless and colour developed in the crystals. None of the cocrystals cited by Aitipamula et al.13 exhibit colour polymorphism, although there are few reports on colour cocrystals despite both the solid components are white in colour,14-15 mostly due to the extensive π-stacking (π-delocalization) in molecular arrangement of both the components. Analysis of the cocrystal structures of both polymorphs revealed differences in the π-stacking patterns of molecules along with their hydrogen bonding interactions and estimation of the gap between the highest occupied molecular orbital (HOMO)

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and lowest unoccupied molecular orbital (LUMO) helped us to arrive at possible reason for their colour difference. The cocrystals of FS with 2BPY and 4AP did not exhibit (colour) polymorphism. The common structural feature observed in all the structures is the formation of sandwich motifs comprising FS and pyridines through π-stacking interactions and its subsequent arrangement in the three dimensions through conventional and weak hydrogen bonding interactions led to different arrangement of molecules. Our finding suggests that even cocrystals are prone to exhibit polymorphism if both components are conformationally flexible.27 This of course will have more impact on the formulations of API as cocrystals of APIs are made to prevent polymorphism of API along with improving their physiochemical properties.28

Figure 1. Molecular structures schemes for cocrystal components, furosemide (FS), 4,4’bipyridine (4BPY), 2,2’-bipyridine (2BPY) and 4-aminopyridine (4AP). All the cocrystals were characterized by 1H NMR spectroscopy (Figures S1-S8, ESI). Experimental Section

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Materials: The API, furosemide (FS) and all other cocrystal components were obtained from Sigma-Aldrich: furosemide (FS) (99%), 4,4’-bipyridine (4BPY) (98%), 2,2’-bipyridine (2BPY) (≥ 99%), and 4-aminopyridine (4AP) (≥ 99%). All the solvents used for the crystallization were of HPLC grade. Cocrystallization: Cocrystallization of equimolar amount of FS and 4BPY, 2BPY, and 4AP was attempted by grinding as well as slow evaporation methods from the solution of almost all common organic solvents at ambient conditions (see supporting information for details on crystallization). The cocrystals obtained from solution crystallization were fully characterized by solution state 1

H NMR spectroscopy, thermal analysis, powder X-ray diffraction and single-crystal X-ray

diffraction analysis (See ESI for data). The grinded samples were characterized using powder Xray diffraction to verify the formation of cocrystals by comparing it with simulated powder pattern from single crystal XRD of cocrystal (Figure S10-S13). The description of the preparation of cocrystals for each case from ethanol is given below. FS−4BPY (1): Equimolar quantities of FS (16.5 mg, 0.050 mmol) and 4BPY (7.8 mg, 0.050 mmol) were weighed, grinded, and dissolved in 1-1.5 ml of ethanol or ethanol-water mixture (1/1; v/v). The solution was then heated to 80-90 °C for 10 min to dissolve the compound completely and kept for crystallization under ambient condition by the slow evaporation method. Cocrystallization of FS with 4BPY in ethanol produced two polymorphs. The form 1I yellow crystals (Figures 2a, S9(a), ESI) appeared within 15-20 hrs whereas form 1II orange crystal (Figures 2b, S9(b), ESI) started to appear after 1- 2 days in the same flask concomitantly (Figure S9(c), ESI). This suggested that the form 1I needles (light yellow) were formed faster, and the

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form 1II blocks (orange) were perhaps formed under thermodynamic conditions. The amount of yellow crystals produced was always more compared to the orange crystals, indicating the preference for yellow crystals during crystallization. Both polymorphs could also be obtained from acetonitrile by slow evaporation in 1-2 days. Seeding the mother liquor (in acetonitrile) with yellow crystals, exclusively produce yellow crystals, however, seeding the mother liquor with orange crystals initially produced more of yellow crystals (form 1I) along with fewer orange crystals (form 1II). Form 1I crystals could also be produced from acetone, methanol, 1-propanol, 2-propanol-water mixture (1/1, v/v) and 1-butanol (Table S1, ESI). Solvates of the FS-4BPY cocrystals with methanol, ethanol, 2-propanol, 1-butanol are reported earlier,25 however none of these cocrystal solvates was produced during the crystallization from these solvents. Ethanol and 2-propanol gave both polymorphs concomitantly whereas methanol and 1-butanol produced only form 1I crystals (Table S1, ESI). Both neat grinding and liquid assisted grinding (with catalytic amount of ethanol) revealed the formation of cocrystal polymorphs, however PXRD pattern also shows the presence of individual diffraction peaks of the FS and 4BPY (Figure S11, ESI). Crystallization from other solvents gave separate crystals of FS and 4BPY (Table S1). FS−2BPY (2): Equimolar quantities of FS (16.5 mg, 0.050 mmol) and 2BPY (7.8 mg, 0.050 mmol) were weighed and grinded for 15-20 minutes. The grinded sample was then dissolved by heating/warming in various solvents and kept standing for 2-3 days for slow evaporation of the solvent at room temperature. All the solvents failed to produce the cocrystals except ethanolwater mixture (2 mL, 1/1, v/v) which gave colorless needles crystals after about 3 days (Figures 2c, S9(d), ESI). In all other solvents both the components were crystallized separately. Both neat grinding and liquid assisted grinding (with the catalytic amount of ethanol) revealed the formation of cocrystals 2 (Figure S12, ESI).

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FS−4AP (3): Equimolar quantities of FS (16.5 mg, 0.050 mmol) and 4AP (4.7 mg, 0.050 mmol) were weighed and grinded for 15-20 minutes. The grinded sample was then dissolved by heating/warming in various solvents and kept standing for 2-3 days for slow evaporation of the solvent at room temperature. Good quality single crystals (colorless blocks) were obtained from acetone-water (1/1, v/v), ethanol-water (1/1, v/v) and acetone-ethanol-water (1/1/1, v/v) mixtures (Figures 2d, S9(e), ESI). Crystallization from ethanol and methanol gave very fine powdery cocrystals, not suitable for single crystal XRD analysis. All other solvents gave separate crystals of both the components. Both neat grinding and liquid assisted grinding (with the catalytic amount of ethanol) revealed the formation of cocrystal 3 (Figure S13, ESI).

(a)

(b)

(c)

(d)

Figure 2. Photographs of cocrystals of FS with pyridines captured using Nikon D5200 camera, (a) FS-4BPY form 1I cocrystals, (b) FS-4BPY form 1II cocrystals, (c) FS-2BPY cocrystals and (d) FS-4AP cocrystals. Details of X-ray diffraction data collection, structure solution and refinement, Differential Scanning Calorimetric (DSC) analysis, Hot Stage Microscopy (HSM) and Powder X-Ray Diffraction (PXRD) studies, DFT Calculations are given in the ESI. Table 1. Summary of the crystallographic data for cocrystals of FS

Crystal Data

FS-4BPY

FS-4BPY

FS-2BPY(2)

FS-4AP(3)

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(form 1I) Formula

C12H11ClN2O5S

Mr Crystal

(form 1II) · C12H11ClN2O5S · 2(C12H11ClN2O5

C12H11ClN2O5S ·

0.5(C10H8N2)

0.5(C10H8N2)

S)· 1.5(C10H8N2)

C5H6N2

408.83

408.83

895.75

424.86

Size, 0.45 × 0.24 × 0.12

0.47 × 0.26 × 0.18 0.38 × 0.22 × 0.48 × 0.32 × 0.19

mm

0.15

Temp. (K)

100 (2)

100 (2)

100 (2)

100 (2)

Crystal Syst.

Monoclinic

monoclinic

triclinic

triclinic

Space Group

C2/c

P21/n

P1ത

P1ത

a/Å

25.981(5)

11.4746(2)

10.2035(2)

8.5913(2)

b/Å

6.5254(13)

9.6630(2)

14.0538(3)

12.9773(3)

c/Å

21.043(4)

16.1003(3)

15.1873(3)

17.6723(4)

α/0

90

90

107.1600(10)°

84.4360(10)°

β/0

107.372(3)

101.215(1)°

107.3050(10)°

84.9390(10)°

γ/0

90

90

91.4320(10)°

75.4550(10)°

V/Å3

3404.8(12)

1751.10(6)

1971.45(7)

1894.01(8)

Z

8

4

2

4

Dcalc/g cm-3

1.595

1.551

1.509

1.490

µ/mm-1

0.384

0.374

0.340

0.350

F(000)

1688

844

926

880

Ab. Correct.

multi-scan

multi-scan

multi-scan

multi-scan

Tmin/ Tmax

0.8460/0.9553

0.8439/0.9358

0.8816/0.9508

0.8500/0.9365

2θmax/°

50

54

56

52

Total reflns.

11426

16425

41374

32197

unique reflns.

2972

3818

9494

7439

Obs. reflns.

2708

3634

8428

6572

h, k, l (min, (-26, 30), (-7, 7), (-14, 14), (-12, (-13, 13), (-18, (-10,

10),

max)

(-24, 25)

12), (-20, 20)

18), (-20, 20)

15),

Rint

0.0242

0.0212

0.0308

0.0289

No. of para

260

254

575

530

(-15,

(-21, 21)

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R1 [I> 2σ(I)]

0.0339

0.0303

0.0438

0.0419

wR2[I> 2σ(I)]

0.0746

0.0780

0.0859

0.0826

R1 [all data]

0.0382

0.0319

0.0518

0.0500

wR2 [all data]

0.0763

0.0796

0.0892

0.0857

goodness-of-

1.159

1.072

1.077

1.120

+0.43, -0.36

+0.46, -0.47

+0.49, -0.45

1041021

1041022

1041023

fit ∆ρmax,

∆ρmin +0.31, -0.42

(eÅ-3) CCDC no.

1041020

Results and Discussion Color Cocrystal Polymorphs of FS-4BPY (1). Cocrystallization of FS and 4BPY was attempted at ambient conditions from almost all the common organic solvents as well as solvent mixtures. Cocrystallization of FS with 4BPY from ethanol, ethanol-water mixture, 2-propanol and acetonitrile yielded the form 1I (yellow, Figures 2a, S9(a), ESI) within a day and form 1II (orange, Figures 2b, S9(b), ESI) crystals after 1-2 days in the same flask concomitantly (Figure S9(c), ESI). This suggests that form 1I needles (light yellow) and form 1II blocks (orange) could have been formed under kinetic and thermodynamic conditions respectively. In all the crystallization attempts the quantity of form 1I crystals was always more compared to the form 1II crystals, specifying the preference for form 1I crystals during crystallization also supplemented by the seeding experiment in acetonitrile solution. Single crystal X-ray analysis revealed that both form 1I and form 1II crystals belong to monoclinic C2/c and P21/n space groups respectively (Table 1). In both polymorphs, the 4BPY molecule occupies the special position (inversion center); thus only half the molecule is present

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in the asymmetric unit, and the inversion operation generates the other half. The occupancy of FS molecule is full in both polymorphs. Thus, the stoichiometry of FS and 4BPY molecules in dimorphs is 2:1 also confirmed by 1H NMR spectroscopy (Figures 3a, S1-S4 ESI). The C–O bond lengths [1.228(2)–1.307(2) Å for form 1I and 1.2365(17)–1.3047(17) for form 1II] in the COOH group of both structures show that proton transfer has not occurred from acid O-H group of furosemide to the N-atom of the bipyridine, which is the most likely occurrence in bipyridine based cocrystals (CSD survey, ESI). The intramolecular geometry of the FS as observed in dimorphs reveals the formation of intramolecular N-H···O hydrogen bonding interactions engaging N-H of the amide moiety and the carbonyl oxygen of the carboxyl group (Figure 3a-b), similar to the polymorphs and other cocrystals of FS.19 The geometrical parameters of intramolecular N-H···O hydrogen bond are similar in both cocrystals polymorphs (Entries 1, 3, Table S2, ESI). Additionally, intramolecular short halogen bonding interaction between the Cl and the sulphonyl oxygen is also observed in dimorph of 1 similar to polymorphs of FS (Entries 2, 4, Table S2, ESI). The overlay of the molecules of FS in both polymorphs reveals that the furan ring shows significant orientational difference in conformation due to the free rotation about N1-C8 bond (C1-N1-C8-C9 torsion, Figure 3c, Table S3, ESI). In form 1I crystals, the furan ring is almost perpendicular to the basal plane of benzene ring (dihedral angle between the plane of benzene and furan is 82°, torsion C1-N1-C8-C9 = -71.3(3)°, Table S3 Figure S14(a), ESI) whereas in form 1II crystals the furan ring is somewhat co-planar (dihedral angle between the plane of benzene and furan is 35°, torsion C1-N1-C8-C9 = 177.5(1)°, Figure S14(b), ESI). Similarly, the sulphonamide groups also showed the almost perpendicular orientational difference in the conformation of amino and SO2 group (Figure 3c, Table S3).

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(a)

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(b)

(c) Figure 3. ORTEPs29 of (a) form 1I and (b) form 1II crystals of 1 displaying intramolecular NH···O and Cl···O interactions and intermolecular O-H···N interaction between FS and 4BPY molecules. The displacement ellipsoids are drawn at 50% probability level and H atoms are shown as small spheres of arbitrary radii and (c) structure overlay of the molecules of FS in cocrystal polymorphs form 1I (yellow) and form 1II (orange). Formation of Common Sandwich Structure The common structural feature observed in both polymorphs is the formation of sandwich centrosymmetric motif through aromatic π···π stacking interactions involving two molecules of FS and one molecule of 4BPY (Figure 4, entries 1, 12 Table S4). However, there are differences in the orientation of FS and 4BPY within the sandwich motif. In form 1I crystals, the orientation of halobenzene and bipyridine is almost collinear (c.a. 5°, Figure S15(a), ESI) whereas the

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orientation differs by c.a. 18-19° in form 1II crystals (Figure S15(b), ESI).

The sandwich

association also paves the way for the generation of C-H···π interactions between 4BPY H-atom and π- electron cloud of the furan in form 1I crystal (Figure 4a, entry 2, Table S4). The perpendicular conformation of furan with respect to the benzene (Figure 14a) in these crystals could be due to its involvement in C-H···π interactions with the 4BPY molecule. The sandwich centrosymmetric assembly in form 1II crystal also brings the π-cloud of the carbonyl group (C=O) of the FS in stacking mode with respect to the π-electron cloud of the pyridine to generate the C=O···π contact (Figure 4b, entry 13 Table S4). The shape of the sandwich assembly also differs in both forms. In form 1I crystals, the sandwich motif is rectangular in shape wherein the N atom of the both pyridine rings extends only to the centroid of the benzene ring, whereas in form 1II crystals it extends close to the Cl atom which gave assembly almost square like shape (Figure 4).

(a)

(b)

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Figure 4. View of sandwich motifs in (a) form 1I and (b) form 1II crystals. In form 1I crystals, the sandwich motif is formed between FS and 4BPY molecules via (i) π···π interactions and (ii) C-H···π interactions whereas in form 1II crystals (i) π···π and (ii) C=O···π interactions are involved in sandwich motif formation. Differences in Stitching of the Sandwich Assemblies In form 1I crystals, the neighboring sandwich motifs are unit translated along the b-axis to create the one dimensional monolayer mainly via N-H···O, O-H···N and C-H···O interactions (Figure 5a, entries 3, 4, 6 Table S4, ESI). Along the monolayer the FS molecules are connected via long and non-linear N2-H2N···O1 hydrogen bond involving H-atom of the amide and hydroxyl oxygen of the carboxyl group (entry 3 Table S4, ESI) along with short dipolar C-Cl···C=O contact (entry 5, Table S4) to create the molecular strings of unit-translated FS molecules. Additionally, each 4BPY molecule of adjacent unit-translated sandwich motifs is also engaged in π-stacking assemblies (entry 7, Table S4) across the inversion center to generate the extended chain within the monolayer. The assembly of FS and 4BPY molecules in the monolayer resembles a ladder structure where molecular strings of FS molecules can be considered as rails and the 4BPY molecules as rungs (Figure 5b). One can also envisage the linear assembly of FS and 4BPY through very short and linear O-H···N interactions engaging the carboxyl O1-H1O group of FS and pyridine N3-atom of the 4BPY (entry 4, Table S4). The linear assembly is also supplemented by short but non-linear C-H···O interaction involving donor C-H of the 4BPY molecule and acceptor carboxyl of FS molecule (Entry 6, Table S4). These two assemblies i.e. sandwich and linear, are part of an extended monolayer structure created by the unit-translated arrangement of molecules along the b-axis. In form 1II crystals, the sandwich motifs are joined

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centrosymmetrically along the a-axis through C-H···O and parallel displayed π···π contacts between the benzene and furan rings of the FS resulting in the formation extended columnar structure (Figure 5c, entry 14, 15, Table S4, ESI).

(a)

(c)

(b)

(d)

Figure 5. Molecular arrangement reveals monolayer formation in form 1I cocrystal (a) and cartoon representation of the same in ladder shape (b), molecules in form 1II cocrystals showing columnar assembly (c) also represented by cartoon in (d). In form 1I crystals FS molecules forms molecular string via rather a weak (i) N2-H2N···O1 and short dipolar C3-Cl1···C7=O2 (ii) interactions. The 4BPY molecules interact with FS rail via (iii) O1-H1O···N3 and (iv) C17-

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Within the monolayer the 4BPY molecules are interacting via (v)

aromatic π···π interactions. In form 1II crystals the adjacent sandwich assemblies are connected via (i) C8-H8B···O3 and (ii) π···π interactions between benzene and furan rings. In form 1I crystals, the adjacent monolayers along the b-axis have two-fold relationship and are loosely connected to each other via weak C-H···Cl contact (entry 8, Table S4, ESI) to generate the bilayer structure (Figure 6a). In contrast, the unit-translated columns in form 1II crystals are strongly held along the b-axis through strong N-H···O interactions between the FS molecules (entry 16, Table S4, ESI) further supplemented by bifurcated C-H···O interactions (entries 17, 18, Table S4, ESI) involving 4BPY H-atoms and sulfonyl oxygen atom of FS to create the 2D compact molecular packing (Figure 6b).

(a) Figure 6. View of molecular packing along the b-axis in (a) form 1I crystals showing linking of the monolayers via (i) C2-H2···Cl1 contacts and (b) form 1II crystals displaying linking of the

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adjacent columns through (i) N2-H2N···O1, (ii) C14-H14···O5 and (iii) C16-H16···O5 interactions. Molecular packing viewed down the two-fold axis (b-axis) in both polymorphs has similar packing arrangements of the sandwich motifs. In form 1I crystals the neighbouring sandwich assemblies have c-glide relation (along c-axis) and are linked through N-H···O interaction (entry 9, Table S4, ESI) engaging sulfonamide groups of FS to generate the layered structure. The layer is further supported by short O···O contact between the furan and sulfonyl oxygens (Figure 7a, entry 10, Table S4, ESI). The adjoining layers along the a-axis are linked through excellent centrosymmetric C-H···π interactions between aminomethyl H-atom and furan ring and the moderate C-H···Cl interactions across the two-fold axis (entries 8, 11, Table S4, ESI). In form 1II crystals, the molecular packing viewed down b-axis revealed bridging of the columnar assembly along the c-axis via O-H···N between carboxyl O1-H1O group and pyridine N3 atom and N-H···O interactions engaging amide N2-H3N group and carboxyl carbonyl oxygen atom O2 (entries 19, 20, Table S4, ESI) having n-glide symmetry relationship to generate 2D packing (Figure 7b). The linking of the columnar assemblies is also supported by two C-H···O interactions (entries 21, 22, Table S4, ESI). Close inspection of the molecular packing in both polymorphs reveals clear differences in the association of both molecules in their cocrystals. In form 1I crystals, both molecules are involved in the formation of a ladder structure (Figure 5a) whereas in form 1II crystals the FS molecule forms a hexamer through conventional N-H···O hydrogen bonding interactions (entries 16, 20, Table S4, ESI) to generate a channel of roughly dimension 7 x 10 Å2 (Figure S16). The open

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channel accommodates the bipyridine molecule through strong O-H···N and π···π interactions (entries 19, 12 Table S4, ESI).

(a)

(b)

Figure 7. View of the molecular packing down b-axis (a) in form 1I crystals and (b) form 1II crystals. In form 1I crystals the sandwich assemblies on the ac plane are linked via long and nonlinear (i) N2-H3N···O5 and (ii) short O3···O4 contacts as well as (iii) C8-H8B···π and (iv) C2H2…Cl1 interactions whereas in form 1II crystals the sandwich motifs are stitched through (i) O1-H1O···N3, (ii) N2-H3N···O2, (iii) C12-H12···O4, (iv) C2-H2···O4 interactions. DSC, HSM and PXRD Studies Differential scanning analysis of form 1I and form 1II crystals showed different behavior. The DSC measurement for form 1I crystals revealed small endothermic hump centered at 189 °C suggesting minor structural phase transition before the melting endotherm observed at 216 °C (Figure 8a) whereas form 1II crystals showed only an endotherm corresponding to its melting at 218 °C (Figure 8b). Overlay of the experimental PXRD patterns of form 1I and form 1II crystals of 1 revealed noticeable structural difference thus confirming their polymorphic nature (Figure S17, ESI). Furthermore, superimposing the experimental PXRD pattern of respective polymorph with their PXRD profile simulated from the single crystal X-ray data confirms

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homogeneity of the sample (Figure S18, ESI). The PXRD pattern of the cooled form 1I crystals, obtained by heating beyond the transition temperature (190 °C), matched the PXRD profile of the form 1II crystals, indicating the conversion of the form 1I to form 1II crystals at the transition temperature (Figure 9). Hot stage microscopy study on polarizing microscope revealed slight change on the crystal surface at the beginning of the transition which continued up to 204 °C which subsequently developed into cracks in the crystals (Figure S19, ESI). Observation of each of the damaged crystals under a polarizing microscope confirmed presence of many tiny single crystalline components into the cracked crystals. The unit cell determination from these fragments was not successful because of their small size. Nevertheless, the PXRD analysis of this process conform the thermal conversion of form 1I crystals to form 1II crystals (Figure 9). In-situ unit cell measurement at different temperatures i.e. 80 °C, 120 °C, 140 °C was successful revealing the unit cell of form 1I crystals. However, the unit cell measurement at 160 °C was not successful due to changes at the crystal interior leading to the loss of single crystallinity as suggested by the observation of the same crystal under the polarizing microscope. The diffraction spots confirmed the crystalline nature, but high mosaicity and bad least squares of the orientation matrix suggested a phase change (this could be responsible for a small endothermic hump in the DSC experiment).

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Figure 8. DSC profiles of (a) form 1I and (b) form 1II crystals.

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Figure 9. Overlay of PXRD patterns of form 1I (blue) and form 1II (orange) and heated cocrystals of form 1I (black) crystals beyond the transition temperature. The PXRD pattern of cooled (after heating) crystals of form 1I matched with PXRD pattern of form 1II crystals. The computation of packing energies30,31 for the dimorphs of 1 gave the values of -267.2 and 231.2 kJ mol-1 for form 1I and form 1II, respectively, indicating that the form 1I crystals are most stable compared to form 1II crystals. Further, the molecular energy calculated from the optimized geometry using DFT method and at the B97D3/6-311G** level reveals that form 1I is indeed having slightly lower energy (-877.091 x 10-3 kJ mol-1) in compared to the form 1II (877.085 x 10-3 kJ mol-1). The values of crystal densities 1.595 g cm-3 (form 1I) and 1.551 g cm-3 (form 1II) are also consistent with the packing energies. This also substantiates the formation of form 1I crystals exclusively in all the crystallization experiments. Using UNI force field computations, approximate energies for the intermolecular potential (sum of Coulombic, polarization, dispersion and repulsion terms as defined in the PIXEL method30,31 and integrated into the program Mercury32 were estimated. The estimation of the intermolecular potential between the molecules involved in sandwich motif formation revealed high value for form 1II crystals (-62.9 kJ/mol, Figure 4b) than form 1I crystals (-51.5 kJ/mol, Figure 4a) indicating the maximum overlap of molecules in form 1II crystals as compared to form 1I crystals. In addition, the intermolecular potential along the monolayer in form 1I crystals gave the values -46.8 kJ/mol and -23.4 kJ/mol for the joining of FS molecules with each other (rail) and bipyridine (rungs) molecules respectively (Figure 5a). The stitching of the monolayers through long C-H···Cl contacts (Figure 6a, entry 8, Table S4, ESI) have the intermolecular potential value -43.8 kJ/mol. Conversely, in form 1II crystals, the sandwich motifs are tightly held along all the three dimensions. The intermolecular potential values for the joining of the sandwich motifs to create

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the columnar structure by their parallel overlap along the a-axis through C-H…O (entry 14, Table S4, ESI) contact including marginal π-stacking interactions between the benzene and furan rings of FS was found to be -55.5 kJ/mol (Figure 5c). The intermolecular potentials values between the molecules engaged in linking of the columns through N-H···O, bifurcated C-H···O interactions (entries 16-18, Table S4, ESI) and marginal C-H···π interaction between the furan C-H atom and benzene ring along the b-axis were found to be -44.1 kJ/mol, -12.0 and -19.8 kJ/mol respectively (Figure 6b). The intermolecular potential values for linking of the sandwich assemblies along the third dimension (ac plane) in both crystal forms were found to be the same (Table S5, ESI). From the above data it is evident that molecules in form 1I crystals are loosely bound to each other either in the sandwich assembly formation, linking of the sandwich assembly to create the monolayer or in the bridging of the monolayers compared to the molecules in form 1II crystals. Mechanism of phase transformation from comparison of molecular packing Although it is difficult to establish the mechanistic alleyway involving accurate molecular motions for the conversion of form 1I crystals to form 1II crystal, some indication can be sought from a comparison of the arrangement of molecules in both crystal forms. The common feature observed in both crystal forms is the formation of zero-dimensional sandwich motifs (Figure 4) where the 4BPY molecule is stacked between two FS molecules. The maximum parallel stacking is observed in form 1II crystals than form 1I crystals, also substantiated by intermolecular potential values. The significant difference between these structures is the stitching of these sandwich motifs to produce the 2D structure. In form 1I crystals, these assemblies are loosely held along the monolayer (b-axis) via long and non-linear N-H···O and dipolar C-Cl···C=O

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contacts (Figure 5a, entries 3, 5, Table S4, ESI) and the neighboring monolayers are joined via weak C-H…Cl (entry 8, Table S4, ESI) contact along the crystallographic two-fold axis (Figure 6a). In contrast, the sandwich motifs in form 1II crystals are strongly held on the ab plane; through C-H···O and π···π interactions (entries 14-15, Table S4, ESI) along the columnar assembly (Figure 5b) and via N-H···O, bifurcated C-H···O (entries 16-18, Table S4, ESI) and off centered C-H···π contacts along the b-axis involved in linking of the columns (Figure 6b). The values of the intermolecular potentials were also found to be more along the columnar assemblies and inter-linking of these assemblies in form 1II crystals as compared to the association of the monolayers in form 1I crystals (Table S5). The interactions in form 1I crystals, within the sandwich motif and its inter-linking are not strong enough to hold the sandwich motifs tightly, at high temperatures they tend to loosen in the lattice near the transition temperature to allow the rearrangement of molecules as in form 1II crystals. Hence, it appears that during the phase transition molecules sacrifice weak contacts in form 1I crystals to attain stronger binding in form 1II crystals. For the conversion of form 1I crystals to form 1II crystals, the FS and the 4BPY molecules within the sandwich motif in form 1I crystals are required to reorient and ‘close in’ themselves with consequent conformation change to achieve the maximum overlap by aligning in parallel mode as observed in form 1II crystals. This change at the sandwich motif in form 1I crystals subsequently breaks the other weak interactions involved in the monolayer formation and its successive connections. Hence relatively weaker association of the sandwich motifs in form 1I crystals seem to be responsible for their transformation to form 1II crystals at high temperature, perhaps through highly disordered phases, since multiple polycrystalline domains (form 1II crystals) are formed from a single crystal of form 1I.

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Careful inspection of the packing patterns of the sandwich motifs revealed that they are closely related (irrespective of their orientation) and differed by only one or two rotation of common assemblies i.e. ‘sandwich motifs’ (morphotrops) thus confirming that it a case of morphotropism.33-34 To visualize these changes, a cartoon representation of the molecular packing pattern is shown in figure 10. Each sandwich motif is represented by capsule comprising both FS molecules as L-shape pattern and 4BPY moiety as small hexagons; a tiny open circle (blue) at the center of the bipyridine represents the inversion center. Green and purple colored ‘L’ and hexagon represents molecule is up and down the plane respectively. The conversion of form 1I crystals (C2/c) to form 1II crystal (P21/n) involves the ‘close in’ of the molecules in sandwich motifs accompanied by conformational change to establish maximum stacking followed by non-crystallographic 90° rotation (clockwise) of every sandwich motif related by 2-fold axis perpendicular to their plane to generate a 21-screw axis between the sandwich motifs which eventually generates the P21/n structure. Such non crystallographic rotation is possible because of the weak association of the sandwich motifs in form 1I crystals that allowed the desired conformational changes in the FS and 4BPY moieties. The values of packing energies and the crystal density suggest that form 1I crystals are more stable than form 1II crystals. Therefore, the transformation of form 1I crystals to form 1II crystals, in general seems to be due to the reorganization of stable crystalline phase into the metastable phase at high temperature. Furthermore, the occurrence of form 1I crystals in all the crystallization attempts suggest that form 1I crystals are more preferred over form 1II crystals. Therefore, the transformation of a stable crystalline phase (form 1I) to a metastable crystalline phase form 1II) at high temperature suggests form 1II crystals being an intermediate phase. This is also supported by a decrease in the crystal density from form 1I to form 1II crystals.

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Figure 10. Topological patterns of the molecular organization during phase transition, (a) assembly of sandwich motifs as depicted in figure 6a, (b) ‘Close in’ of the molecules in sandwich motifs accompanied by conformational change. Such molecular motions are possible because of the loose connection of molecules within sandwich assembly as well as in its linking in other dimensions. (c) Non-crystallographic 90° rotation (clockwise) of every sandwich motifs related by two-fold axis perpendicular to their plane to generate a two-fold screw axis between them to generate P21/n structure depicted in figure 7b. Intermolecular interactions in cocrystal polymorphs of 1 were quantified via Hirshfeld surface analysis35-37 (Figure S20, ESI) using CrystalExplorer.38 All the intermolecular interactions involved in form 1I and form 1II crystals of 1 were evaluated with respect to their contribution to the overall stability of the cocrystal structure. Hirshfeld surfaces and fingerprint plots were also generated for the cocrystal polymorphs to evaluate their differences. The dissimilarity in the

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Hirshfeld fingerprint images for the both polymorphs are readily distinguishable, evidently indicating a different molecular environment in the two cocrystals structures (Figure S21) and also validates the high sensitivity of this method for the comparison of polymorphic structures.3940

Among the interactions present in both forms, H···H, H···O, H…N and C···C made major

contributions to the Hirshfeld surface areas (for the contribution of each of these contacts in lattice stabilization see supporting information). The solid state UV-Vis spectrum in transmittance mode of form 1I and form 1II shows absorption at different wavelengths. The form 1I shows λmax at 438 nm while form 1II crystals reveal it at 536 nm indicating red-shift of the absorption in form 1II crystals compared to the form 1I crystals (Figure 11 and Figure S23). To rationalize the yellow (form 1I) and orange (form 1II) color of the cocrystal polymorphs we performed DFT calculations to estimate the band gap in these two polymorphic cocrystals. The HOMO-LUMO gap values estimated from theoretical calculations (B97D3 basis set with 6-311G**) compared well with the experimental UV-vis experiments (Table S6, Figure S24, ESI). The calculated value of λmax for form 1I crystals is 455 nm while, for the form 1II, the value is 548 nm. The results obtained from B3LYP/6-31G** level of theory lacking the dispersion correction term, underestimated the λmax values; 289 mm and 328 nm for form 1I and form 1II, respectively. The lower band gap in form 1II crystals compared to form 1I crystals revealed optimization of the donor–acceptor interactions which essentially leading to the color change of form 1I crystals from yellow to orange in the form 1II crystals. It is to be also noted that the dipole moment values obtained from the B97D3/6-311G** level calculation are found to be 7.7 D for form 1I and 8.9 D for form 1II.

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Figure 11. UV−visible spectra of the solid sample of form 1I (black) and form 1II (red) crystals in transmission mode. Cocrystal (2) FS-2BPY Cocrystal 2 crystallized in the triclinic P-1 space group. Asymmetric unit contained two different conformers of FS having full occupancy along with three molecules of 2BPY each having half occupancies (Figure 12a). All three 2BPY molecules occupy the special position (inversion center) so that only half the molecule is present in the asymmetric unit, and the inversion operation generates other half. Thus, the stoichiometry of FS with 2BPY is 2:1.5. Symmetry independent FS molecules are labeled as primed and unprimed. Similarly, 2BPY molecule associated with primed FS molecule is labeled as unprimed and vice versa. The third 2BPY molecule is labeled as unprimed that showed slight orientational disorder over two positions having occupancy 0.55 and 0.45. The C–O bond lengths [1.223(2)–1.332(2) Å for conformer 1

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and 1.227(2)–1.326(2) for conformer 2] in the COOH group of both structures shows that proton transfer hasn’t taken place from acid O-H group of FS to the N-atom of the 2BPY revealing it is the cocrystal (Figure 12a). The intramolecular geometry of both FS molecules observed in cocrystal 2 is similar to the cocrystals 1 (Figure 12a, entries 5-8, Table S2, ESI). The conformation of the furan ring in both FS molecules shows the orientation difference of about 70-80° with respect to the basal plane of the benzene ring due to the free rotation about N1-C8 bond (C1-N1-C8-C9 torsion, Table S3, Figure S25, ESI). The overlay of both conformational isomers (primed and unprimed) of FS reveals that the furan ring shows slight orientational difference (13-14°) due to the free rotation about C8-C9 (C8’-C9’) bond (N1-C8-C9-O3 or N1’C8’-C9’-O3’torsion). Similarly, the sulphonamide groups in both the molecules also showed noticeable differences (c.a. 106°) in the orientation of amino and SO2 groups (Figure S26, ESI). Like polymorphs of 1, both molecules in 2 also involved in centrosymmetric sandwich assembly formation comprising two molecules of FS and one molecule of 2BPY. Thus both FS conformers (primed and unprimed) form their respective sandwich motif each engaging one molecules of 2BPY (Figure 12b, see Figure S27, ESI for primed sandwich motif). Unlike form 1I crystals of 1, the orientation of halobenzene and 2BPY in the sandwich motif differ significantly by about 58-62° (Figure S28, ESI). The shape of the sandwich motif is of a square type similar to the form 1II crystals.

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(a)

(b)

Figure 12. (a) ORTEP of asymmetric unit in cocrystal 2 displaying intramolecular N-H···O and Cl···O and intermolecular O-H…N interaction between FS and 2BPY molecules. The displacement ellipsoids are drawn at 50% probability level and H atoms are shown as small spheres of arbitrary radii and (b) view of sandwich motifs in cocrystal 2 formed by unprimed molecules of FS and 2BPY. The sandwich motif is formed between FS and 2BPY molecules via C=O…π interactions between carbonyl group of the FS and π-cloud of the 2BPY molecule across the inversion center. Similar sandwich motif is formed by primed molecules of FS and 2BPY (Figure S27, ESI). Molecules within the sandwich motifs are loosely associated via C=O···π interactions involving C=O of the carboxyl groups and pyridine ring of the 2BPY and other hydrophobic forces (Entries 1, 2, Table S7, ESI). In fact, carboxyl group of both FS molecule overlaps with pyridine rings of 2BPY molecule resulting in parallel displaced overlap of FS and 2BPY molecules in the sandwich assembly (Figure 12b, Figure S27, ESI). Both these sandwich assemblies formed by symmetry independent FS and 2BPY molecules are arranged alternately along the a-axis to create the monolayer similar to the form 1I crystals (Figure 13a). Along the monolayer, the symmetry independent FS molecules are joined via strong N-H···O interactions

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involving N-H of the sulfonamide group and O of the sulfonyl group (Entries 3, 4, Table S7). The N-H···O linked 1D molecular string of FS is further supplemented by the three C-H···O interactions (entries 5-7, Table S7, Figure 13). However, unlike form 1I crystals, the 2BPY molecules of neighboring sandwich motif within the monolayer do not associate via π···π interactions, although it has comparable stacking arrangement to generate the one-dimensional extended chain within the monolayer. Similar to the form 1I crystals, the arrangement of molecules of FS and 2BPY in the monolayer resemble to a ladder-like structure wherein chain of FS molecules can be judged as rails and the 2BPY molecules as rungs (Figure 13a). One can also imagine the separate linear assembly of FS and 2BPY (formed by symmetry independent molecules) through very short and linear O-H···N interactions within the monolayer involving FS of the next sandwich motif (primed or unprimed) and 2BPY of the previous sandwich motif (unprimed or primed). The linear assembly engages the carboxyl O-H group of FS and pyridine N-atom of the 2BPY to generate O-H···N interactions (Entries 8, 9, Table S7, Figure 13). Each linear assembly of symmetry independent molecules gets support from weaker C-H···O interactions formed between 2BPY and FS molecules (Entries 10-13, Table S7, ESI, Figure 13a). These two assemblies i.e. sandwich and linear, are part of an extended monolayer structure created by the arrangement of two symmetry independent FS and 2BPY molecules along the aaxis. The neighboring monolayers along the c-axis are strongly connected via moderate centrosymmetric N-H···O interactions involving amide N2’-H2’N and oxygen O5 of the sulfonamide group and short and linear halogen bonding contact (C-Cl···O) between Cl1 and oxygen O5 of the sulfonamide group to generate the compact 2D packing on ac plane (Entries 14, 15, Table S7, ESI Figure 13b).

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(b)

Figure 13. (a) Molecular arrangement reveals monolayer formation identical to ladder like structure in cocrystal 2 through N-H···O, O-H···N and C-H···O interactions. Within the monolayer the symmetry independent FS molecules are connected through (i) N2-H2N···O4’, (ii) N2’-H3’N···O4, (iii) C8-H8B···O2’, (v) C10-H10’···O3 and (v) C8’-H8’B···O2 interactions. The rungs 2BPY molecules are bridging the rails of FS via (vi) O1’-H1’O···N3, (vii) O1H1O···N3’, (viii) C13-H13···O2’, (ix) C16-H16···O1’, (x) C13’-H13’···O2 and (xi) C16’H16’···O1 interactions. (b) Linking of the adjacent monolayers along the c-axis via centrosymmetric bifurcated (i) N2’-H2’N···O5 and (ii) C3-Cl1···O5 contacts. Molecular packing viewed down the monolayer (a-axis) reveals joining of individual sandwich assemblies of symmetry independent molecules through short C···O (entry 16, Table S7, ESI) contacts to create the columnar assembly along the c-axis similar to form 1II crystals (Figure 14a). Each sandwich assemblies are connected with respective assemblies (primedprimed and unprimed-unprimed) in different fashion along the b-axis. The primed sandwich

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motifs are connected via C-H···O and C-H···N interactions (Entries 17-18, Table S7, ESI) across the inversion center to generate the layered structure along the b-axis. The primed sandwich motifs are also joined with each other along the b-axis through two molecules of the third 2BPY via two C-H···O interactions (Entries 19-20, Table S7, ESI). Both these 2BPY molecules are above and below the layer of sandwich assemblies on the bc plane (Figure 14b). In contrast, the unprimed sandwich motifs are not linked to each other directly however they are connected through third 2BPY molecules across the inversion center via N-H···N, C-H···O and C-H···N interactions (Entries 21-23, Table S7, ESI and Figure 14). These unprimed sandwich motifs create the void to accommodate the third 2BPY molecule along the b-axis. The unprimed 2BPY molecule also interacts with the third 2BPY molecule along the channel via moderate C-H···N interactions (Entry 24, Table S7, ESI and Figure 14).

The orientation of the third 2BPY

molecules is almost perpendicular to the unprimed 2BPY molecule along the channel.

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Figure 14. Packing of the sandwich motifs on the bc plane. Along the c-axis the sandwich assemblies are loosely joined via short (i) C2···O3’ short contact while along the b-axis they are connected via (ii) C11’-H11’···O4’, (iii) C12’-H12’···N2’. The primed and unprimed sandwich

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assemblies along the b-axis are connected differently through third 2BPY molecule. The primed sandwich motifs are connected through two molecules of 2BPY via (iv) C18-H18···O5’ and (v) C20’-H20’···O5 interactions whereas unprimed sandwich motifs are bridged through third 2BPY molecule via (vi) N2-H3N···N4 and (vii) C18-H18···O4 interactions. The unprimed 2BPY molecule also interacts with third 2BPY molecule through (viii) C15-H15···N4 interactions, (b) cartoon representation of (a) showing association of sandwich assemblies of primed and unprimed molecules. Differential scanning analysis of cocrystal 2 revealed only the single endotherm attributed to its melting at 127.9 °C and thus rules out the possibility of structural phase transition before melting (Figure S29, ESI). The overlay of the experimental PXRD pattern of cocrystal 2 with its PXRD profile simulated from the single crystal X-ray data matched well thus confirming the homogeneity of the sample (Figure S30, ESI). The computation of packing energies for the cocrystal 2 revealed value -732.2 constituted by total five clusters each cluster having individual packing energies -83.15 kJ mol-1, -119.97 kJ mol-1, -202.96 kJ mol-1, -120.16 kJ mol-1 and -205.98 kJ mol-1. Using UNI force field computations, approximate energies for the intermolecular potential were estimated. Intermolecular potential associated with both the sandwich motifs formed by primed and unprimed molecules have similar values i.e. -45.0 and -47.8 kJ/mol (Figure 12b and Figure S27). However, FS molecules engaged in the molecular string (rail of the ladder structure) generation through N-H···O interactions within the monolayer (Figure 13a) is the strongest association between the primed and unprimed molecules and gets the first rank with intermolecular potential values -70.0 kJ/mol and -69.0 kJ/mol. This indicates that FS and 2BPY molecules within the monolayer are strongly associated unlike form1I crystals where the molecules with the

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monolayer are loosely connected. The averaging of the intermolecular potentials involved in joining of the monolayers along the c-axis through bifurcated primed-unprimed and unprimedunprimed pairing via N2’-H2’N···O5 and C3-Cl1···O5 contacts (Figure 13b) is ranked third with approximate value -18.9 kJ/mol.

The second rank intermolecular potential is between the

molecules involved in joining of the individual sandwich assembly in generating columnar structure along the c-axis via short C2···O3’ contact with value -41.7 kJ/mol (Figure 14). The joining of the columns along the b-axis gets the lowest rank with intermolecular potentials values lay in the range -10 to -15 kJ/mol (Figure 14, Table S8, ESI). Cocrystal (3) FS-4AP Crystal structure of FS-4AP belongs to triclinic P-1 space group containing two molecules of each in the asymmetric unit, thus the stoichiometry of FS and 4AP in the cocrystal is 1:1 (Figure 15(a), ESI). The C–O bond lengths of the carboxyl group in both the conformational isomers of FS lay in the range 1.259–1.267 Å confirming that proton transfer has occurred from carboxyl group to the N-atom of the 4AP indicating cocrystal 3 is ionic (Figure 15a). The intramolecular geometry of both FS is similar to that observed in cocrystals 1 and 2 (Entries 9-12, Table S2, ESI, Figure 15a). The overlay of the both FS conformers reveals that the furan ring shows significant orientational difference in conformation due to the free rotation about N1-C8 and N1’-C8’ bond (C1-N1-C8-C9/C1’-N1’-C8’-C9’ torsion, Table S3, ESI, Figure S31, ESI). In conformer 1 (unprimed), the torsion C1-N1-C8-C9 is very near to planar (-172.5°) whereas in conformer 2 (primed) the torsion C1’-N1’-C8’-C9’ has acquired the almost perpendicular value (63.67°, Table S3, ESI). When the orientation of furan ring in both conformers is compared with the basal plane of benzene ring, the difference in the conformation was found to be 70° and 87° for unprimed and primed FS molecule respectively (Figure S32, ESI).

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Similar to cocrystal polymorphs of FS-4BPY (1) and FS-2BPY (2), molecules in FS-4AP (3) also constitute a sandwich motif however with the difference. In cocrystals 3, two FS molecules accommodate two molecules of 4AP. Both 4AP molecules within the sandwich assembly are linked to FS molecules via aromatic π···π interactions to create a chain via π···π contacts between FS-4AP-4AP-FS tetramer (Entries 1-3, Table S9, ESI Figure 15b).

(a)

(b)

Figure 15. (a) ORTEP of asymmetric unit in cocrystal 3 displaying intramolecular N-H···O and Cl…O and intermolecular N-H···O interactions between FS and 4AP molecules. The displacement ellipsoids are drawn at 50% probability level and H atoms are shown as small spheres of arbitrary radii and (b) view of sandwich motifs in cocrystal 3 comprising both symmetry independent molecules of FS and 4AP. The sandwich motif is formed between FS and 4AP molecules via π···π interactions between benzene and pyridine rings as shown.

These sandwich assemblies are linked through the centrosymmetric C-H···π interactions across the inversion center involving C-H of the furan ring and π-cloud of the benzene to create the columnar structure roughly along the b-axis (Entries 4-5, Table S9, ESI, Figure 16). Both FS molecules form C-H···π interactions with the respective molecules across the inversion center,

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however, the geometry of the C-H···π linked dimer is different. The unprimed molecules make planar geometry whereas the primed molecules generate S-shape geometry. The S - shape geometry is further supported by C-H···O interaction between the FS molecules engaging furan C-H and carboxyl oxygen moieties (Entry 6, Table S9, ESI). The neighboring columns along the c-axis are centrosymmetrically linked across the inversion center via three N-H···O, C-H···O and C-H···N interactions involving N-H and C-H moieties of FS and 4AP and acceptors O and the N atoms of sulfonamide moiety of FS to generate the 2D packing (Entries 7-11, Table S9, ESI, Figure 16a). The adjacent columns are also connected differently along the c-axis engaging centrosymmetrically related FS molecules via N-H···O, C-H…O and C-H···π interactions to generate compact 2D packing on the bc plane (Entries 12-15, 17-21, Table S9, ESI, Figure S33).

(a)

(b)

Figure 16. (a) Packing of the sandwich motifs on the bc plane. Roughly along the b-axis the sandwich assemblies are joined via two different centrosymmetric C-H···π interactions involving

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symmetry independent FS molecules to generate columnar assembly. Unprimed molecules generate flat C10-H10···π (Cg2) dimer (i) whereas the primed molecules create S-shape C12’H12’···π (Cg4) dimer (ii) supported by (iii) C11’-H11’···O2’ interactions. The adjacent columns along the c-axis are connected via (iv) N1’-H1’N···O4, (v) N4’-H6’N···O4, (vi) N4-H6N···O4’, (vii) C12-H12···O4’, (viii) C17’-H17’···N2’ interactions. (b) Cartoon representation of the (a) showing linking of the adjacent columns. Careful observation of the packing arrangement of FS molecules reveals formation of layered arrangement by both FS molecules (primed and unprimed) along a-axis. Both FS molecules are linked via N-H…O hydrogen bonds to generate respective tetrameric assembly, the extension of which along the a-axis generates monolayer structure (Entries 13, 17, 22, 23, Table S9, ESI, Figure S34). The adjacent monolayers along the b-axis are linked centrosymmetrically through C-H···O and C-H···π interactions to generate the bilayers (Entries 4-6, 24 Table S9, ESI, Figure S34). Both these bilayers (of primed and unprimed FS molecules) run in a parallel fashion along the c-axis to create the voids for accommodating both 4AP molecules (Figure S35, ESI). View of this molecular packing down the c-axis reveals the arrangement of sandwich assemblies generating layered structure. Differential scanning analysis of cocrystal 3 revealed only the single endotherm corresponding to its melting observed at 218 °C and thus rules out the possibility of structural phase transition before melting (Figure S36, ESI). The overlay of the experimental PXRD pattern of cocrystal 3 with its PXRD profile simulated from the single crystal X-ray data matched well thus confirming the homogeneity of the sample (Figure S37, ESI).

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The estimation of the packing energy gave the values -563.1 kJ/mol comprising packing energy values of four clusters (-90.02 kJ/mol, -82.60 kJ/mol, -193.36 kJ/mol and -197.17 kJ/mol). Averaging the intermolecular potential values for the sandwich motifs (Figure 15b) comprising two molecules of FS and two molecules of 4AP was found to be -38.2 kJ/mol (intermolecular potential for unprimed FS and 4AP is -46.5 kJ/mol, for primed FS and 4AP it is -45.0 kJ/mol and for primed 4AP- unprimed 4AP it is -23.1 kJ/mol). The intermolecular potential associated with the FS molecules engaged in H-bonded 1D polymer formation is the weakest one with values -24.4 kJ/mol and -20.7 kJ/mol for unprimed and primed molecules respectively (Figure S34). However stitching of these molecular strings along the b-axis resulting in the formation of tetramer and subsequently the monolayer structure has strongest intermolecular potential values -52.8 kJ/mol and -55.4 kJ/mol for the unprimed and primed molecules respectively (Figure S34). The generation of the bilayers by bridging of the monolayers through C-H…π interactions gave larger intermolecular potential value -46.2 kJ/mol for unprimed molecules than primed molecules -38.4 kJ/mol (Figure S34). Conclusions Cocrystal formation of FS, a loop diuretic drug with pyridines has been reported and thoroughly characterized using relevant solid-state characterization tools. Cocrystals of FS with 4BPY revealed colour cocrystal polymorphism yellow (form 1I) and orange (form 1II) albeit both the FS and the cocrystal former are colourless. The common structural features observed in all the cocrystals is the formation of sandwich motifs constituted by FS and pyridine molecules mostly through aromatic π-stacking interactions. Also the sandwich motif in form 1II crystals also facilitated the formation of C=O···π interaction between the C=O group and benzene ring of FS.

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The contribution of both aromatic π-stacking and C=O···π interactions in form 1II crystals in the formation of sandwich motif aid in attaining the maximum overlap of FS and pyridine molecules.

These sandwich motifs are linked in three dimensions via N-H···O, O-H···O, O-

H···N, C-H···O, C-H···N, C-H···π and π···π interactions to generate the overall packing in all the cocrystals. The difference in the colour of form 1I and form 1II crystals could be attributed to the differences in the π···π* separation between the benzene ring of FS and pyridine ring of 4BPY also substantiated by DFT calculations. DSC, HSM and XRD analyses revealed irreversible crystal-to-crystal thermal phase transition of form 1I to form 1II crystals confirming the monotropic relationship between the two phases. The structural similarity between the polymorphs was attempted from the knowledge of morphotropism. The conformational flexibility of FS in both polymorphs contributed greatly to the polymorphism of cocrystals. It suggests that making cocrystals is not the cure for restricting the polymorphism of conformationally flexible molecules like FS. Similar to the polymorphism of single component drug which helps in tuning the physicochemical properties of API, the polymorphism in cocrystals may also have equal impact in altering the properties like solubility, dissolution rate, bioavailability, stability etc. The cocrystallization studies of FS with other analogous of bipyridines are currently being explored in our laboratory to investigate the plausible formation cocrystals through π-stacking assemblies and their subsequent consequence on color development. ASSOCIATED CONTENT Supporting Information. Characterization data for cocrystals 1-3 including 1H NMR, DSC, PXRD, hot stage microscopy, crystallization, intermolecular interactions, torsion angle, HOMO-

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LUMO gap and potential tables, crystal photomicrographs, structural overlay, packing diagrams, Hirshfeld surface plots, HOMO-LUMO orbital view, solid-state UV spectra and CSD database survey. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author *[email protected]. Ph No. 020-25902225, Fax No. 020-25902642 Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Funding Sources This work was made possible by financial support from CSIR (ORIGIN) Notes The authors declare no competing financial interest. ACKNOWLEDGMENT ES and RLG thank CSIR for fellowship. SHT thanks, CSIR (INDIA) for a project fellowship under the ORIGIN program of 12FYP. We gratefully acknowledge Dr. Ms. S. Mule for her kind support in carrying out the DSC measurements. We also thank Mr. Plawan K. Jha and Mr. Anthony Devdass for recording the solid-state UV spectra and Mr. Yashpal Yadav for grabbing the crystal photographs.

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ABBREVIATIONS FS: Furosemide 4BPY: 4,4’bipyridine 2BPY: 2,2’-bipyridine 4AP: 4-aminopyridine REFERENCES 1. Stahly, G. P. Cryst. Growth Des. 2009, 9, 4212–4229. 2. Desiraju, G. R. CrystEngComm 2003, 5, 466–467. 3. Aakeröy, C. B.; Salmon, D. J. CrystEngComm 2005, 7, 439− 448. 4. Bond, A. D. CrystEngComm 2007, 9, 833–834. 5. Aitipamula, S.; Banerjee, R.; Bansal, A. K.; Biradha, K.; Cheney, M. L.; Choudhury, A. R.; Desiraju, G. R.; Dikundwar, A. G.; Dubey, R.; Duggirala, N.; Ghogale, P. P.; Ghosh, S.; Goswami, P. K.; Goud, N. R.; Jetti, R. R. K. R.; Karpinski, P.; Kaushik, P.; Kumar, D.; Kumar, V.; Moulton, B.; Mukherjee, A.; Mukherjee, G.; Myerson, A. S.; Puri, V.; Ramanan, A.; Rajamannar, T.; Reddy, C. M.; Rodriguez-Hornedo, N.; Rogers, R. D.; Row, T. N. G.; Sanphui, P.; Shan, N.; Shete,G.; Singh, A.; Sun, C. C.; Swift, J. A.; Thaimattam, R.; Thakur, T. S.; Thaper, R. K.; Thomas, S. P.; Tothadi, S.; Vangala, V. R.; Variankaval, N.; Vishweshwar, P.; Weyna, D. R.; Zaworotko M. J. Cryst. Growth Des. 2012, 12, 2147–2152. 6. Aakeröy, C. B., Fasulo, M. E., Desper, J. Mol. Pharm. 2007, 4, 317-322. 7. Almarsson, Ö.; Zaworotko, M. J. Chem. Commun. 2004, 7, 1889−1896. 8. Vishweshwar, P.; McMahon, J. A.; Joanna, A. B.; Zaworotko, M. J. J. Pharm. Sci. 2006, 95, 499−516. 9. Shan, N.; Zaworotko., M. J. Drug. Discovery Today 2008, 13, 440−446.

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24. Khandavilli, U. B. R.; Gangavaram, S.; Goud, N. R.; Cherukuvada, S.; Raghavender, S.; Nangia, A.; Manjunatha, S. G.; Nambiarc, S.; Pal, S. CrystEngComm 2014, 16, 4842– 4852. 25. Surov, A. O.; Simagina, A. A.; Manin, N. G.; Kuzmina, L.G.; Churakov, A. V.; Perlovich G. L. Cryst. Growth Des. 2015, 15, 228−238. 26. Srirambhatla, V. K.; Kraft, A.; Wattb, S.; Powell, A. V. CrystEngComm 2014, 16, 9979– 9982. 27. Lemmerer, A.; Adsmond, D. A.; Esterhuysen, C.; Bernstein J. Cryst. Growth Des. 2013, 13, 3935−3952. 28. Reddy, L. S.; Babu, N. J.; Nangia, A. Chem. Commun. 2006, 1369−1371. 29. Farrugia, L. J. J. Appl. Cryst. 2012, 45, 849–854. 30. Gavezzotti, A., Acc. Chem. Res. 1994, 27, 309–314. 31. Gavezzotti, A.; Filippini, G. J. Phys. Chem., 1994, 98 (18), 4831–4837. 32. Macrae, C. F.; Bruno, I. J.; Chisholm, J. A.; Edgington,P. R.; McCabe

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For Table of Contents Use Only

Furosemide Cocrystals with Pyridines: An Interesting Case of Colour Cocrystal Polymorphism Ekta Sangtani, Sanjay K. Sahu, Shridhar H. Thorat, Rupesh L. Gawade, Kunal K. Jha, Parthapratim Munshi, and Rajesh G. Gonnade* a Furosemide, a loop diuretic drug commonly used for the treatment of hypertension and edema yielded colour cocrystal polymorphs yellow and orange concomitantly with coformer 4, 4’bipyridine albeit both the API and the cocrystal former are colorless. The significant color difference between the two polymorphs could be attributed to the different π-stacking patterns between the two molecules and differences in their HOMO-LUMO gap. A yellow cocrystal form displayed crystal-to-crystal structural thermal phase transition to the orange cocrystal.

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