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Crystal Structures of Pyrogallol, its Hydrate, and Stable Multiple Z' Cocrystals with N-Heterocycles Containing Metastable Conformers of Pyrogallol Ranjit Thakuria, Suryanarayan Cherukuvada, and Ashwini Nangia Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/cg3003367 • Publication Date (Web): 06 Jul 2012 Downloaded from http://pubs.acs.org on July 10, 2012

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Crystal Growth & Design

Crystal Structures of Pyrogallol, its Hydrate, and Stable Multiple Z' Cocrystals with N-Heterocycles Containing Metastable Conformers of Pyrogallol Ranjit Thakuria, Suryanarayan Cherukuvada, and Ashwini Nangia* School of Chemistry, University of Hyderabad, Prof. C. R. Rao Road, Gachibowli, Central University, P.O., Hyderabad 500 046, India E-mail: [email protected]

Abstract: The solid-state structural landscape of bioactive compound pyrogallol (1,2,3benzenetriol) is studied. We report crystal structures of pyrogallol, its 0.25 hydrate, and a few cocrystals with aromatic N-heterocycles. The hydroxyl groups of pyrogallol can adopt different conformations in the gas phase and in crystalline modifications, e.g. stable conformer ‘A’ in pyrogallol and its hydrate, whereas metastable conformer ‘C’ in cocrystals with isonicotinamide and nicotinamide. The occurrence of high Z' (maximum of 5 quinoline and 3 pyrogallol molecules in cocrystal 6a) and variable stoichiometry of components in cocrystals (e.g. pyrogallol–isonicotinamide 1:2 and 2:1 in 4a and 4b, pyrogallol–quinoline 3:5 and 2:3 in 6a and 6b) is a unique and novel observation in these structures. Grinding and slurry experiments confirmed that the high Z' cocrystal is quite stable and it does not transform to a low Z' higher symmetry structure. Given the biological and pharmacological functions of pyrogallol, a naturally occurring ingredient of the Indian gooseberry, solubility and dissolution rates of pyrogallol and its cocrystals were compared in water.

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Introduction Pyrogallol, chemical name benzene-1,2,3-triol (also pyrogallic acid), is an active ingredient of Emblica officinalis, the Indian gooseberry, which is extensively used across Asia in traditional medicine for its anti-inflammatory and anti-pyretic properties.1 Pyrogallol is a powerful reducing agent and is used as an indicator of the amount of oxygen in the air and dry N2 lines, in the absorption of moisture, and as a dying material. It was used as a developing agent in the early days of photography.2 There is a renewed interest in the pharmaceutical properties of pyrogallol as a superoxide anion generator and in inducing cell apoptosis.3 Pyrogallol is being explored as a drug candidate for non-small cell lung cancer (NSCLC)4 and cystic fibrosis (CF)1 with promising results. The hydroxyl groups of pyrogallol can form intramolecular hydrogen bonds (Scheme 1) to give several conformers5 of this rigid, planar molecule. Gier et al. predicted five conformers of pyrogallol of which conformer ‘A’ and conformer ‘C’ were calculated to be the lowest energy structures.5 Conformer ‘A’ (with 2 intramolecular hydrogen bonds) is about 1664 cm–1 (4.76 kcal mol–1) more stable than conformer ‘C’ (with only one intramolecular H bond)5 due to cooperative hydrogen bonding.6 Conformers ‘D’, ‘E’ and ‘B’ have higher energy due to interatomic repulsion and absence of intramolecular H bonds. The energy ranking of conformers is ‘A’ < ‘C’ < ‘D’ < ‘E’ < ‘B’ in the gaseous state. In the absence of further computational data, this energy order is taken in the solid-state with the justification that the stability of conformers is due to intramolecular H bonding and interatomic repulsion terms which are also present in the solid-state. Quite surprisingly, in spite of its long history and bioactivity, there is no systematic study of pyrogallol crystal structures and its solid-state properties, such as hydration, solubility, stability, etc. Surprisingly, there is no crystal structure report of native pyrogallol despite its antiquity to 1786.2 The unit cell parameters of pyrogallol were reported by Becker et al. in 1972.7 We describe in this paper crystal structures of native (guest-free) pyrogallol and its 0.25 hydrate as well as eight cocrystals of pyrogallol with N- heterocycle bases (Scheme 2). O

H

H O

O

O O

H

O H A

O

H

O

O H C

H

H

O

O

H H

O E

D

H

O

H O

H H

H O B

Scheme 1 Intramolecular hydrogen bonding in pyrogallol conformers. Conformer ‘A’ with 2 H bonds and no H-H repulsion is the most stable conformation.


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N H N

NH2 O

O

NH2

O

O

N

N NH2

N 4,4'-Bipy

N

N 2-Hqu

N Pza

Nico

Isonico

Quin

1: Pyro guest free 2: Pyro-H2O (1:0.25) 3: Pyro-Pza (1:1) 4a: Pyro-Isonico (1:2) 4b: Pyro-Isonico (2:1) 5: Pyro-Nico (2:1) 6a: Pyro-Quin (3:5) 6b: Pyro-Quin (2:3) 7: Pyro-2-Hqui (1:2) 8: Pyro-Bipy-H2O (2:3:2)

OH OH

OH Pyro

Scheme 2 Molecular structures of coformers used in this study and product cocrystals 3-8.

Results and Discussion Single crystals of 1–7 were obtained by solution crystallization in ethyl acetate−toluene mixture (1:1 v/v) and cocrystal 8 was crystallized from acetonitrile. Alcohols and phenols have been reported to crystallize in high Z' structures8 and pyrogallol is no exception. Our crystallization experiments resulted in the formation of high Z' and variable stoichiometry adducts, some of these structures contained metastable conformers of pyrogallol. Liquid-assisted grinding was employed to prepare cocrystals9 in the bulk phase. Solubility and dissolution of pyrogallol and its nicotinamide and isonicotinamde cocrystals in water was studied. These high Z' cocrystal structures were found to be quite stable to aqueous slurry conditions. Crystal structures Pyrogallol guest-free 1. Becker et al. reported the unit cell parameters of pyrogallol and a hydrate but 3D coordinates and molecular arrangement in the crystal lattice are not known.7 Crystallization of pyrogallol from ethyl acetate−toluene (in 1:1 v/v) at room temperature resulted in plate-shaped crystals of the guest-free structure 1, whose space group and cell parameters (Table 1) matched with the reported values. In the crystal structure of pyrogallol, all three hydroxyl groups are on the same side (conformer ‘A’). The molecules form an O– H···O helical trimer synthon along the [010] axis (Figure 1a) and the phenyl rings are stacked at ~3.4 Å through π···π interactions. The helical trimer motif of pyrogallol molecules result in an infinite tape parallel to (–101) plane with neighboring tapes filling the space (Figure 1a). Hydrogen bonds are listed in the Supporting Information (Table S1).



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Powder X-ray diffraction (PXRD) of commercial pyrogallol (Merck) did not match completely with the calculated lines of the anhydrate crystal structure 1 (Figure 2) even though the compound was pure by NMR (see Experimental Section). A hydrate form of pyrogallol was also isolated and characterized. Pyrogallol 0.25 hydrate 2. Cocrystallization of pyrogallol and pyrazinamide in 1:1 ratio and with isonicotinamide in 2:1 ratio from ethyl acetate−toluene (1:1 v/v) independently gave crystals of two different morphologies: needle crystals in tetragonal space group P42/n which were characterized as pyrogallol 0.25-hydrate 2, and block crystals of the respective cocrystals (discussed next). In the crystal structure of 0.25-hydrate the water molecule is disordered around the crystallographic inversion centre with a site occupancy factor of 0.5, along with two pyrogallol molecules (of conformer ‘A’) in the asymmetric unit. The crystal structure stoichiometry is therefore 0.25 water per pyrogallol molecule. Water molecules make a channel along the [001] axis in the centre of a helical tetrameric synthon of pyrogallol molecules connected through O–H···O hydrogen bonds (Figure 1b and c). Re-examination of the PXRD pattern of commercial pyrogallol now showed hydrate 2 impurity in what was believed to be guest-free 1 (Figure 2). The commercial material (from a 3 years old bottle) was found to contain 34% hydrate content by TGA and KF analysis (Table 2). The guest-free material was obtained by controlled dehydration at 80 °C and melt crystallization (Figure S1, Supporting Information). A heat-cool-reheat DSC cycle of the melt phase showed recrystallization to the guest-free material upon cooling which upon reheating showed a clean melting endotherm at 134 °C (Figure 3a). The guest-free material 1 completely converted to the hydrate form upon water-assisted grinding (see Figure S2, Supporting Information), and this method was used to reproduce the bulk material. This transformation confirms the tendency of pyrogallol to hydrate during handling and storage. The presence of water in crystal structure 2 was confirmed by DSC, TGA, hot stage microscopy (HSM) and KF titration. The endotherm at 75 °C in DSC is due to water release prior to the melting endotherm at 134 °C (Figure 3b). A weight loss of 3.18% (calc. for 0.25hydrate 3.12%) in TGA (Figure 3b) matches with a quarter water molecule. The thermal events were visualized in hot stage microscopy images (Figure 4).


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Table 1 Crystallographic parameters. Crystal Data

1a

2b

3

4a

4b

Formula unit

C6H6O3

C6H6O3–(H2O)0.25

C6H6O3–C5H5N3O

C6H6O3–(C6H6N2O)2

(C6H6O3)2–C6H6N2O

Formula wt.

126.11

130.61

249.23

370.36

374.34

Crystal system

Monoclinic

Tetragonal

Triclinic

Monoclinic

Triclinic

T [K]

100(2)

100(2)

100(2)

100(2)

100(2)

a [Å]

12.1144(11)

24.5039(12)

6.687(9)

17.056(2)

9.2540(8)

b [Å]

3.7765(3)

24.5039(12)

7.074(9)

5.8142(7)

9.5435(9)

c [Å]

13.1365(12)

3.7849(4)

11.721(16)

18.163(2)

10.0539(9)

α [°]

90

90

80.61(2)

90

72.4640(10)

β [°]

115.484(1)

90

87.92(2)

100.886(2)

83.730(2)

γ [°]

90

90

76.02(2)

90

80.092(1)

Volume [Å3]

542.52(8)

2272.6(3)

530.8(12)

1768.7(4)

832.47(13)

Space group

P21/n

P42/n

P1

P21

P1

No. of independent

4

8

2

2

2

Z'

1

2

1

2

1

Z"

1

2.5

2

6

3

Zr

1

2

2

2

2

4

20

4

12

6

1.544

1.527

1.559

1.391

1.493

general positions

Z –3

Dcalc [g cm ]

5

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µ/mm−1

0.126

0.126

0.121

0.104

0.117

Reflns. collected

5197

21853

4997

18448

8725

Unique reflns.

1075

2263

1859

7006

3277

Observed reflns.

1019

2211

1422

4733

3022

R(int)

0.0234

0.0548

0.0658

0.0946

0.0230

R1 [I>2σ(I)], wR2

0.0372, 0.0981

0.0788, 0.1512

0.0779, 0.2035

0.0644, 0.1192

0.0389, 0.0950

GOF

1.064

1.335

1.106

1.006

1.064

a

Pyrogallol crystal structure was reported in Ref. 7 (CSD Refcode – PYRGAL) with no 3D coordinates determined

b

Pyrogallol hydrate structure was reported in Ref. 7 (CSD Refcode – QQQBKD) with no 3D coordinates determined

Crystal Data

5

6a

6b

7

8

Formula unit

(C6H6O3)2–C6H6N2O

(C6H6O3)3–(C9H7N)5

(C6H6O3)2–(C9H7N)3

C6H6O3–(C9H7NO)2

(C6H6O3)2–(C10H8N2)3–(H2O)2

Formula wt.

374.34

1024.10

639.68

416.42

756.80

Crystal system

Monoclinic

Triclinic

Triclinic

Triclinic

Triclinic

T [K]

100(2)

100(2)

100(2)

100(2)

298(2)

a [Å]

11.2860(13)

8.0271(16)

7.5553(8)

7.6809(7)

9.3257(10)

b [Å]

19.551(2)

16.182(3)

11.6292(13)

10.0076(9)

9.5756(10)

c [Å]

7.8342(9)

20.306(4)

18.763(2)

13.4348(12)

24.020(3)

α [°]

90

74.727(3)

88.645(9)

73.3500(10)

91.162(2)

β [°]

108.082(2)

86.151(4)

80.688(9)

82.756(2)

95.450(2)

γ [°]

90

85.632(4)

76.572(10)

84.385(2)

116.545(2)

6


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Volume [Å3]

1643.3(3)

2534.1(9)

1582.2(3)

979.43(15)

1905.4(4)

Space group

P21/c

P1

P1

P1

P1

No. of independent

4

2

2

2

2

Z'

1

1

1

1

1

Z"

3

8

5

3

7

r

2

2

2

2

3

12

16

10

6

14

Dcalc [g cm ]

1.513

1.342

1.343

1.412

1.319

−1

µ/mm

0.118

0.091

0.091

0.100

0.093

Reflns. collected

16948

24276

11772

10078

20031

Unique reflns.

3256

8908

5541

3773

7513

Observed reflns.

2579

5640

3185

3356

4614

R(int)

0.0521

0.0885

0.0750

0.0220

0.0294

R1 [I>2σ(I)], wR2

0.0445, 0.1010

0.1158, 0.2072

0.0429, 0.0754

0.0411, 0.1048

0.0642, 0.1588

GOF

1.051

1.128

0.826

1.059

1.024

general positions

Z Z

–3

Z' = Number of formula units in the asymmetric unit; Z" = Number of crystallographically non-equivalent molecules of any type in the asymmetric unit; Zr = Number of different types of chemical residues; Z = Z" × Number of independent general positions.

7



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Table 2 Water content analysis by TGA and KF. Material

TGA

KF

Pyrogallol 0.25 hydrate

3.2%

3.3%

Pyrogallol commercial (Merck)

1.1%

1.3%

3 year old sample

(i.e. 34% of 0.25 hydrate + 66% of anhydrate)

(a)

(b)

(c)

Figure 1 (a) O–H···O helical trimer synthon of pyrogallol molecules make infinite tapes parallel to the (–101) plane in guest-free structure 1. (b) Hydrogen bonded O–H···O tetrameric synthon of pyrogallol forms a water channel (c) along [001] in 2.


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Figure 2 Comparison of PXRD pattern of commercial pyrogallol (middle) with the calculated lines from the X-ray crystal structure of guest-free 1 (above) and 0.25-hydrate 2 (below). The commercial material is a 2:1 mixture of anhydrate plus hydrate (see Table 2).

(a)

(b)

Figure 3 (a) Heat-cool-reheat cycle DSC of pyrogallol guest-free material obtained from the melt. (b) DSC (black) and TGA (red) of (a) pyrogallol 0.25-hydrate 2.



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25 °C

75 °C

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80 °C

131 °C

Figure 4 HSM snapshots of pyrogallol 0.25-hydrate 2. The crystal is stable at 25 °C, it began to opaque at 75-80 °C on heating, and melting occurred at about 131 °C (m.p. of pyrogallol).

Pyrogallol−Pyrazinamide 1:1 cocrystal 3. Cocrystallization of pyrogallol and pyrazinamide in 1:1 ratio from ethyl acetate−toluene (1:1 v/v) resulted in the formation of block-shaped crystals of pyrogallol–pyrazinamide cocrystal 3 in 1:1 stoichiometry. Needle-shaped crystals of pyrogallol 0.25-hydrate 2 crystallized concomitantly (confirmed by its morphology and unit cell check). The crystal structure of 3 (in space group P 1 ) contains a molecule of pyrogallol (conformer ‘A’) and pyrazinamide in the asymmetric unit. Pyrogallol and pyrazinamide form tetrameric synthons of graph set notation10 R22 (10), R44 (12) and R44 (22) via O–H···O, N–H···O and O–H···N hydrogen bonds. Such molecular tapes are connected through π···π interactions (Figure 5a-c).

(a)

(b)

(c) Figure 5 (a) R22 (10), R44 (12) and R44 (22) ring motifs in cocrystal 3. (b) Tetrameric synthon of pyrogallol and pyrazinamide molecules. (c) Offset stacking of adjacent layers.


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Pyrogallol–Isonicotinamide 1:2 cocrystal 4a. Due to lesser number of acceptor groups in isonicotinamide (two compared to three in pyrazinamide), cocrystallization was attempted in 1:2 stoichiometry in ethyl acetate−toluene solvent (1:1 v/v). A 1:2 stoichiometry cocrystal of pyrogallol and isonicotinamide 4a was obtained with 2 molecules of pyrogallol (in high energy conformer ‘C’) and 4 molecules of isonicotinamide in the asymmetric unit. The crystal structure of 4a was solved in Sohncke (chiral) space group P21. Symmetry-independent isonicotinamide molecules form a catemer along the [010] axis (Figure 6a). Isonicotinamide and pyrogallol molecules are connected to such catemer units through O–H···O and N–H···O hydrogen bonds (Figure 6b). The chiral arrangement of achiral molecules in 4a is driven by helical hydrogen bonding.

(a)

(b)

Figure 6 (a) The catemer synthon formed by the isonicotinamide molecules along [010] in cocrystal 4a. (b) Flanking pyrogallol and isonicotinamide molecules are connected to the catemer through O–H···O and N–H···O hydrogen bonds.

Pyrogallol–Isonicotinamide 2:1 cocrystal 4b. Cocrystallization in the reverse ratio of components (2:1) in ethyl acetate–toluene (1:1 v/v) afforded 2:1 cocrystal 4b in space group P 1 . Both pyrogallol molecules reside in the metastable conformer ‘C’. In addition to the block-type crystals of 4b, needle-shaped crystals of pyrogallol 0.25-hydrate 2 were also obtained. The molecular packing and hydrogen bonding in 4a and 4b are completely different. While 4a is a chiral structure with two unidirectional catemer networks between two symmetry-independent isonicotinamide molecules, 4b has a centrosymmetric structure but without any dimer or catemer synthon between isonicotinamide molecules. All strong donor and acceptor groups are fully used in crystal structure 4b (Figure 7a-d).



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(a)

(b)

(c)

(d)

Figure 7 (a–d) Different hydrogen bond synthons in cocrystal 4b.

Pyrogallol–Nicotinamide 2:1 cocrystal 5. Cocrystallization of pyrogallol and nicotinamide in 2:1 ratio in ethyl acetate–toluene (1:1 v/v) gave cocrystal 5 in the same stoichiometry taken. The crystal structure was solved in space group P21/c with two pyrogallol molecules in conformers ‘C’ and ‘D’. The crystal structure lacks the common dimer or catemer hydrogen bond network. Two pyrogallol molecules are hydrogen bonded to nicotinamide (Figure 8a). One pyrogallol (conformer ‘C’, green) and nicotinamide molecules form a layer motif and a symmetry independent pyrogallol which is inclined (conformer ‘D’, blue) connects to the next layer through O–H···O hydrogen bonds. The aromatic rings are separated at 3.26 Å (Figure 8b-c). A plausible reason for the occurrence of high energy conformers ‘C’ and ‘D’ of pyrogallol could be to satisfy strong intermolecular H bonding between the molecules at the cost of fewer intramolecular O–H···O hydrogen bonds. Cocrystallization of pyrogallol and nicotinamide in 1:2 ratio showed a 0.5:2 stoichiometry of components in the difference electron density maps but the X-ray structure could not be properly solved and refined.

(a)

(b)


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(c) Figure 8 (a) Hydrogen bonded synthon in cocrystal 5 (symmetry-independent molecules are colored differently) (b) The molecular layers of pyrogallol and nicotinamide (green) are connected by a second pyrogallol (blue) via O–H···O hydrogen bonds. (c) Overall packing in cocrystal 5 viewed down [001] axis.

Pyrogallol–Quinoline 3:5 cocrystal 6a. Cocrystallization of pyrogallol with quinoline (a liquid at room temperature) by adding a solution of quinoline (1 mL of quinoline in 50 mL of 1:1 v/v ethyl acetate–toluene mixture) to 50 mg of pyrogallol resulted in two different stoichiometry cocrystals 6a and 6b from different batches. Pyrogallol crystallized in conformer ‘A’ and ‘C’ in the two crystal structures. Cocrystal 6a was solved in space group P 1 with three pyrogallol and five quinoline molecules in the asymmetric unit. The crystal structure was analyzed as consisting of two sub-units: part 1 contains two molecules of pyrogallol (conformers ‘A’ and ‘C’) and three molecules of quinoline and part 2 contains one pyrogallol (conformer ‘A’) and two quinoline molecules. Pyrogallol molecules are connected through an infinite tape of O–H···O hydrogen bonds in part 1 and the flanking hydroxyl groups of pyrogallol are connected to three symmetry-independent quinoline molecules via O–H···N hydrogen bonds (Figure 9a and 9b). In part 2, pyrogallol molecules form a centrosymmetric O–H···O dimer synthon and the terminal hydroxyl groups are connected to two symmetry independent quinoline molecules through O–H···N hydrogen bonds (Figure 9c). There are π···π stacks along the [100] axis (Figure 9d).



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(a)

(b)

(c)

(d)

Figure 9 (a) Infinite O–H···O hydrogen bond tape of pyrogallol connects three symmetryindependent quinoline molecules through O–H···N hydrogen bond (part 1). (b) A single unit of part 1 to show hydrogen bonds between pyrogallol and quinoline molecules. (c) Part 2 with the pyrogallol O–H···O dimer synthon connecting quinoline molecules. (d) Overall packing with parts 1 and 2 colored differently.

Pyrogallol–Quinoline 2:3 cocrystal 6b. Cocrystal 6b of pyrogallol-quinoline was obtained from a different batch of 1:1 v/v ethyl acetate–toluene mixture. Cocrystal 6b was solved in space group P 1 with two pyrogallol and three quinoline molecules in the asymmetric unit. Cocrystal 6b has similar structural organization and conformers of pyrogallol (‘A’ and ‘C’) to 6a. Part 1 has one molecule of pyrogallol (conformer ‘A’) and quinoline. Pyrogallol molecules assemble in an infinite stack of O–H···O hydrogen bond chain along [100] axis and one of the terminal hydroxyl groups is hydrogen bonded to quinoline through O–H···N interaction. In part 2, one pyrogallol (conformer C) and two quinoline molecules are H bonded. The two symmetry-independent quinoline molecules are connected to the terminal hydroxyl groups of pyrogallol through O–H···N hydrogen bond. Parts 1 and 2 are π···π stacked in the crystal structure (Figure 10a-c).


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(a)

(b)

(c)

Figure 10 (a) Part 1 containing infinite O–H···O hydrogen bonded chain along [100] axis. (b) Part 2 with discrete O–H···N H bonds between pyrogallol and quinoline. (c) Overall packing to show the two parts in different colors.

Pyrogallol–2-Hydroxyquinoline 1:2 cocrystal 7. Cocrystallization of pyrogallol and 2hydroxyquinoline in 1:2 ratio (based on fewer acceptor groups in 2-hydroxyquinoline) in ethyl acetate–toluene (1:1 v/v) resulted in cocrystal 7 in the same stoichiometry engaged (space group P 1 ). 2-Hydroxyquinoline, in its lactam-lactim tautomeric form, resulted in a non-centrosymmetric amide dimer synthon of R22 (8) graph set. Pyrogallol (conformer ‘A’) is connected to the lactam dimer motif through O–H···O hydrogen bond in a tape along [100] axis. 2-Hydroxyquinoline molecules are π···π stacked at ~3.4 Å distance (Figure 11a-c).

(a)

(b)

(c)



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Figure 11 (a) Lactam tautomer dimer of 2-hydroxyquinoline connected to pyrogallol through O–H···O hydrogen bond. (b) O–H···O hydrogen bond between pyrogallol and lactam O of three adjacent layers. (c) Infinite tape of pyrogallol connecting the π···π stacked 2hydroxyquinoline layers along the [100] axis.

Pyrogallol–Bipyridine·H2O 2:3:2 cocrystal hydrate 8. Cocrystallization of pyrogallol with 4,4'-bipyridine in 2:3 ratio (consistent with 3 OH donors and 2 pyridine acceptors) from acetonitrile resulted in block-shaped crystals of 8 which were solved in space group P 1 containing two pyrogallol (conformer ‘C’), three bipyridine, and two water molecules in the asymmetric unit. The inclusion of water is serendipitous. An O–H···O tetrameric synthon of

R44 (8) graph set between two water molecules and two crystallograophic pyrogallol molecules (Figure 12a) is connected to three bipyridine molecules through O–H···N hydrogen bond in a layer motif. The molecular arrangement of near-neighbor stacks is shown in Figure 12b.

(a)

(b)

Figure 12 (a) O–H···O tetrameric synthon between pyrogallol and water is connected to 4,4'bipyridine molecules flanking on the sides through O–H···N hydrogen bonds. (b) Pyrogallol– bipyridine layers are connected through weak herringbone T-motif of aromatic rings.

Liquid-assisted grinding Cocrystals were prepared in bulk quantity by liquid-assisted grinding9 to carry out solubility and dissolution measurements. About 500 mg of the pure components were mixed in stoichiometric amount found in the crystal structure and ground for 15-20 min in mortarpestle with 8-10 drops of ethyl acetate added. PXRD of the ground material was recorded to confirm complete reaction of starting materials and formation of a new crystalline phase. The powder X-ray diffraction patterns of cocrystals prepared by LAG matched well with the calculated lines from the X-ray crystal structures (Figures S3-S7, Supporting Information), thereby confirming the purity of the bulk phase in each case.


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Solubility and dissolution Due to wide-ranging biological and pharmacological activity of pyrogallol, such as anti-inflammatory,1a anti-pyretic,1b anti-cancer,3,4 and also as a bioactive phenol in Emblica officinalis,1 the solubility and dissolution of pyrogallol and its cocrystals were measured. Solubility and dissolution of the compounds were determined by HPLC (see Experimental Section). The equilibrium solubility of pyrogallol in water is very high (620 mg/mL by HPLC and 610 mg/mL by UV-Vis spectrometry). The reported solubility in Merck Index is 1 g/1.7 mL (or 590 mg/mL).2 After isolating and characterizing the 0.25 hydrate of pyrogallol by Xray diffraction, we now know that this solubility value actually corresponds to that of pyrogallol hydrate since the undissolved material after 24 h of the aqueous solubility experiment was confirmed to be pyrogallol 0.25 hydrate by PXRD pattern match (with reference to Figure S2, Supporting Information). The molar equivalent solubility of pyrogallol in isonicotinamide cocrystals 4a and 4b (150 and 320 mg/mL respectively) and nicotinamide cocrystal 5 (420 mg/mL) is low due to the lower solubility of coformers (isonicotinamide 0.58 mg/mL,11 nicotinamide 500 mg/mL12) compared to that of pyrogallol (610 mg/mL). The cocrystals follow the coformer solubility rule,13 i.e. the lower solubility coformer resulted in a less soluble cocrystal. Isonicotinamide cocrystals are less soluble than nicotinamide cocrystal all of which have lower solubility than pyrogallol. The physical form stability of all three cocrystals was good; they were intact and stable to dissociation/ hydration after 24 h in the wet slurry conditions of solubility measurement in water, as observed by the PXRD of the undissolved materials (with reference to Figures S4–S6, Supporting Information). Generally, cocrystals which are formed of components that have a large differences in solubility tend to dissociate in solution.11 The remarkable stability of pyrogallol–isonicotinamide cocrystals 4a and 4b could be due to solution complexation and energetics favored by strong heteromolecular interactions. Dissolution measurements were carried out in water. The percentage of pyrogallol dissolved in 30 min was calculated as: pure pyrogallol 90%, pyrogallol–nicotinamide 33%, pyrogallol–isonicoinamide (2:1) 20%, pyrogallol–isonicotinamide (1:2) 11% (Figure 13). The intrinsic dissolution rates (IDRs) followed the order pyrogallol 34.75 (mg/cm2)/min, pyrogallol–nicotinamide

7.62

(mg/cm2)/min,

2:1

pyrogallol–isonicotinamide

2

3.21

2

(mg/cm )/min, and (1:2) pyrogallol–isonicotinamide 1.35 (mg/cm )/min. The dissolution curves of cocrystals parallel their solubility trend. Generally with alteration in the number of coformer molecules, solubility and dissolution of a multi-component solid tend to vary.14 With an increase in the number of isonicotinamide molecules in the crystal lattice from one to four (in 2:1 and 1:2 cocrystals), the solubility and dissolution rate decreased consistent with the lower solubility of isonicotinamide coformer.



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Figure 13 Dissolution profile of pyrogallol and its cocrystals 4a, 4b and 5 in water.

High energy conformers and multiple Z' structures Conformationally flexible molecules can crystallize in high energy conformers and with multiple molecules in the asymmetric unit (high Z' structures).8b,15 The hydroxyl groups of pyrogallol render this otherwise rigid molecule to exhibit different conformers with variation in their intramolecular hydrogen bonding (Scheme 1). A survey of the Cambridge Structural Database16 showed that all reported structures of pyrogallol with H atoms and 3D coordinates determined contain the stable conformer ‘A’ except curcumin–pyrogallol cocrystal,17 which contains pyrogallol in its high energy conformer ‘E’. Out of ten crystal structures analyzed in this study, six contain metastable conformer ‘C’ including a cocrystal with ‘D’ conformer of pyrogallol. Moreover, they crystallized with multiple molecules/ conformers in the crystallographic unit cell (high Z'). Hydroxyl group conformations of pyrogallol in crystal structures 1–8 are listed in Table 3. The stable conformer ‘A’ is exclusively found in the guest-free structure, in 0.25-hydrate, and in cocrystals 3 and 7. Conformer ‘A’ coexists with high energy conformer ‘C’ in cocrystals 6a and 6b. Four crystal structures have high energy conformers of pyrogallol exclusively. For multi-component crystal structures with high Z', the term Z" is used to indicate the total number of crystallographically non-equivalent molecules of whatever type in the asymmetric unit.18 Recently, a new notation Zr was proposed to indicate the different types of chemical residues in the crystal lattice.19 The Z numbers for pyrogallol cocrystals are listed in Table 1 along with


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crystallographic parameters. A sub-database of high Z' crystal structures is updated periodically.20 A mismatch of H bonding donor/acceptor groups between the coformers appears to be a factor for the crystallization of high energy conformers of pyrogallol and high Z' in these crystal structures. It is possible that strong H bond acceptors such as pyridine N and amide O in the coformers strengthen hydrogen bonding but that this occurs at the expense of efficient close packing. This conflict could result in the crystallization of multiple molecules. The crystallization solution contains pyrogallol conformer ‘A’ (major) along with minor amounts of less stable conformers ‘C’, ‘D’, etc. The inclusion of high energy conformers (with fewer intramolecular H bonds) during crystallization is to satisfy the demands of maximal intermolecular hydrogen bonding with coformer functional groups and to accommodate more number of H bonds per molecule. These factors can give rise to high Z", pseudosymmetry crystal structures. Generally, the stabilization of high energy conformers and high Z' structures is achieved through stronger intermolecular interactions and better close packing (systematic effect).15,21 The high energy conformers of pyrogallol and high Z' structures are stabilized by strong heteromolecular interactions. The strong H bonds result in the crystallization of achiral molecules in non-centrosymmetric space group with a high Z" of 6 in cocrystal 4a. We feel that crystallization of high energy conformers in these crystal structures is not just a simplistic kinetic explanation proposed in the recent literature, such as crystals on the way,22a fossil relic,8c synthon evolution,22b etc. since multiple Z" cocrystals containing high energy conformers exclusively (such as 4a, 4b, 5 and 8) were found to be reproducibly formed in grinding experiments. More importantly, they were quite stable to the aqueous slurry conditions of solubility and dissolution experiments. One would normally expect kinetic cocrystals to dissociate in aqueous slurry conditions.

Table 3 Pyrogallol conformers in the crystal structures 1–8. Structure

Pyrogallol conformer

1

Conformer ‘A’

2

Conformer ‘A’

3

Conformer ‘A’

4a

Conformer ‘C’

4b

Conformer ‘C’

5

Conformer ‘C’ and ‘D’

6a

Conformer ‘A’ and ‘C’

6b

Conformer ‘A’ and ‘C’

7

Conformer ‘A’



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Conformer ‘C’

8

Conclusions We report the first crystal structures of native pyrogallol and its hydrate with 3D coordinates and H atom positions determined. Cocrystallization of pyrogallol with Nheterocycle bases led to the perturbation of its intramolecular hydrogen bonds to give different conformers of pyrogallol in crystalline adducts. High energy conformers ‘C’ and ‘D’ of pyrogallol were crystallized in the solid-state for the first time. The stable and metastable conformers (‘A’ and ‘C’) of pyrogallol occur about equally often in the present structures (six structures each) and high energy conformer D is present in one structure. Several cocrystals contain more than two molecules in the asymmetric unit (high Z") and could be crystallized in multiple stoichiometry. The presence of OH donors on three contiguous atoms of the phenyl ring in pyrogallol and the strong hydrogen bonding requirements of OH group guide the intermolecular H bonding and crystal packing. Thus frustration between the conflicting needs to achieve maximal intramolecular hydrogen bonding (as in conformer ‘A’) vs. maximal intermolecular H bonding (such as in conformer ‘C’) result in variable stoichiometry and high Z' crystal structures. Cocrystal 4a in chiral space group P21 contains 6 molecules (Z") compared to 3 molecules for centrosymmetric case 4b. However, it is difficult to give a general explanation for the occurrence of high Z' in crystal structures. What is clear from the above structural and experimental results is that what were believed to be kinetically locked metastable structure are more like the thermodynamic minimum. Cocrystallization in multiple ratios under different crystal growth conditions should be worth exploring and will shed further light on understanding structures and stability of high Z' crystals.

Experimental Section Materials and Methods Pyrogallol and Pyrazinamide were purchased from Merck Chemical Co. and used without further purification. All other chemicals were of analytical or chromatographic grade. Water purified from a deionizer cum mixed bed purification system was used in the experiments. 1

H NMR (DMSO-d6): δ 6.20 (2H, s), 6.36 (1H, s), 7.97 (1H, s), 8.75 (2H, s).

13

C NMR (DMSO-d6): δ 107.46 (2C), 118.82 (1C), 133.50 (1C), 146.68 (2C).

Crystallization Pyrogallol guest-free 1: 25 mg of commercial pyrogallol was dissolved in warm ethyl acetate−toluene mixture (1:1 v/v of 5 mL each) and left for slow evaporation at room temperature. Colorless plate crystals were obtained after a few days upon solvent evaporation.


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Pyrogallol 0.25 hydrate 2: Needle crystals of pyrogallol hydrate were obtained upon cocrystallization of pyrogallol with pyrazinamide (in 1:1 ratio) and isonicotinamide (in 2:1 ratio) in ethyl acetate−toluene mixture (1:1 v/v of 6 mL each), independently, along with the cocrystals. Pyro-Pza 1:1 cocrystal 3: 25 mg (0.2 mmol) of pyrogallol and 24 mg (0.2 mmol) of pyrazinamide were dissolved in warm ethyl acetate−toluene mixture (1:1 v/v of 8 mL each) and left for slow evaporation at room temperature. Block crystals of 3 along with needle crystals of pyrogallol hydrate 2 were obtained concomitantly after a few days upon solvent evaporation. Pyro-Isonico 1:2 cocrystal 4a: 12.5 mg (0.1 mmol) of pyrogallol and 24 mg (0.2 mmol) of isonicotinamide were dissolved in warm ethyl acetate−toluene mixture (1:1 v/v of 6 mL each) and left for slow evaporation at room temperature. Plate crystals of 4a were obtained after a few days upon solvent evaporation. Pyro-Isonico 2:1 cocrystal 4b: 25 mg (0.2 mmol) of pyrogallol and 12 mg (0.1 mmol) of isonicotinamide were dissolved in warm ethyl acetate−toluene mixture (1:1 v/v of 8 mL each) and left for slow evaporation at room temperature. Block crystals of 4b along with needle crystals of pyrogallol hydrate 2 were obtained concomitantly after a few days upon solvent evaporation. Pyro-Nico 2:1 cocrystal 5: 25 mg (0.2 mmol) of pyrogallol and 12 mg (0.1 mmol) of nicotinamide were dissolved in warm ethyl acetate−toluene mixture (1:1 v/v of 6 mL each) and left for slow evaporation at room temperature. Plate crystals of 5 were obtained after a few days upon solvent evaporation. Pyro–Quin cocrystals 6a & 6b: To 1 mL of quinoline in 50 mL of 1:1 v/v ethyl acetate– toluene mixture, 50 mg (0.4 mmol) of pyrogallol was added and dissolved by warming the solution. Two different stoichiometry cocrystals 3:5 (6a) and 2:3 (6b) one with needle and the other with plate morphology were obtained from different batches upon solvent evaporation at room temperature. Pyro–2-Hqui 1:2 cocrystal 7: 12.5 mg (0.1 mmol) of pyrogallol and 29 mg (0.2 mmol) of hydroxyquinoline were dissolved in warm ethyl acetate−toluene mixture (1:1 v/v of 6 mL each) and left for slow evaporation at room temperature. Plate crystals of 7 were obtained after a few days upon solvent evaporation. Pyro–Bipy–H2O 2:3:2 cocrystal 8: 25 mg (0.2 mmol) of pyrogallol and 45 mg (0.3 mmol) of bipyridine were dissolved in 10 mL warm acetonitrile and left for slow evaporation at room temperature. Block crystals of 8 were obtained after a few days upon solvent evaporation. X-ray Crystallography X-ray reflections were collected at 100 K (except 8 at 298 K) on Bruker SMART APEX CCD equipped with a graphite monochromator and Mo-Kα fine-focus sealed tube (λ = 0.71073 Å).



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Data integration was done using Bruker SAINT. Intensities were corrected for absorption using SADABS. Structure solution and refinement were carried out using SHELX-97. The hydrogen atoms were refined isotropically and the heavy atoms were refined anisotropically. N–H and O–H hydrogens were located from difference electron density maps and C–H hydrogens were fixed using HFIX command in SHELX-TL. Packing diagrams were prepared in X-Seed. Powder X-ray Diffraction PXRD of the samples were recorded on Bruker D8 Advance diffractometer using Cu-Kα Xradiation (λ = 1.54056 Å) at 40 kV and 30 mA. Diffraction patterns were collected over a 2θ range of 5-50° at a scan rate of 1° min–1. Powder Cell 2.4 was used to plot diffraction patterns. Thermal Analysis DSC was performed on a Mettler Toledo DSC 822e module and TGA on a Mettler Toledo TGA/SDTA 851e module. The typical sample size is 3-5 mg for DSC and 8-12 mg for TGA. Samples were placed in crimped but vented aluminum pans for DSC and open alumina pans for TGA and were purged by a stream of dry nitrogen flowing at 50 mL/min. HSM was performed on a Wagner & Munz PolythermA Hot Stage and Heiztisch microscope. A Moticam 1000 (1.3 MP) camera supported by software Motic Image Plus 2.0ML was used to record images. Equilibrium Solubility and Intrinsic Dissolution Measurements Prior to solubility and dissolution measurements, standard curves of the compounds were obtained spectrophotometrically for λmax 266 nm (of pyrogallol) using a Thermo Scientific Evolution 300 UV-Vis spectrometer. Since both isonicotinamide and nicotinamide absorb at 266 nm, a HPLC method was used to deduct their contribution to the cocrystal and determine the molar equivalent solubility and % dissolution of pyrogallol. HPLC was done on Shimadzu Prominence model LC-20AD equipped with a PDA detector and C-18G Column (250 mm × 4.6 mm ID, 5 µm particle size and 120 Å pore size). Elution was achieved by water and acetonitrile in a gradient method from 10% to 50% acetonitrile in 15 min with a flow rate of 0.5 ml min–1. The retention times of standard aqueous solutions of pyrogallol, nicotinamide and isonicotinamide were found to be 13.6, 9.5 and 9.0 min respectively and the same were observed for the cocrystals (Figures S8–S11, Supporting Information). Pyrogallol has 12, 30 and 33% HPLC peak areas in 4a, 4b and 5 cocrystals respectively. The quantification of pyrogallol in the test solutions obtained from equilibrium solubility and dissolution experiments was done by comparison of the HPLC peak area with that of the standards. Equilibrium solubility was determined in water using the shake-flask method.23 Excess amount of the powdered material was added to 5 mL of water, and the resulting suspension was stirred at room temperature for 24 hr. The suspension was then filtered through 2.5 µm


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Whatman filter paper and the concentration of the resultant solution was determined. Equilibrium solubility of pyrogallol was also obtained by UV-Vis spectrophotometry (ε = 0.67 /mmol/cm). IDR measurements were carried on a USP-certified Electrolab TDT-08L Dissolution Tester by disk intrinsic dissolution method.24 For IDR experiments, 200 mg of pure pyrogallol and the cocrystals 4a, 4b and 5 each were taken in the intrinsic attachments and compressed to a 0.5 cm2 disc using a hydraulic press at a pressure of 2.5 ton inch–2 for 5 min. The intrinsic attachments were placed in jars of 900 mL water preheated to 37 °C and rotated at 50 rpm. 5 mL aliquots were collected at specific time intervals and concentrations of the aliquots were determined with proper dilution from the pre-determined calibration curves. The linear region of the dissolution profile (regression > 0.99) was used to determine the IDR of the compound as [slope of the amount dissolved ÷ surface area of the pellet] per unit time. There is no transformation of pyrogallol cocrystals upon compression as well as after solubility and dissolution experiments as confirmed by PXRD profile of the residue. All pyrogallol solutions including that of cocrystals turned brown at the end of experiments, which was attributed to pyrogallol degradation/ oxidation products (noted in Merck Index2) and observed as extra peaks in the HPLC (Supporting Information).

Acknowledgements R.T. and S.C. thank the UGC and ICMR for fellowship. We thank the DST (JC Bose fellowship, SR/S2/JCB-06/2009) and CSIR (Pharmaceutical Cocrystals, 01(2410)/10/EMR-II) for research funding, and DST (IRPHA) and UGC (PURSE grant) for providing instrumentation and infrastructure facilities.

Supporting Information Available PXRD plots, HPLC trace, and hydrogen bonds table, and crystallographic .cif files are available free of charge via the Internet at http://pubs.acs.org.

References 1. (a) Nicolis, E.; Lampronti, I.; Dechecchi, M. C.; Borgatti, M.; Tamanini, A.; Bianchi, N.; Bezzerri, V.; Mancini, I.; Giri, M. G.; Rizzotti, P.; Gambari, R.; Cabrini, G., Int. Immunopharm. 2008, 8, 1672. (b) Perianayagam, J. B.; Sharma, S. K.; Joseph, A.; Christina, A. J. M. J. Ethnopharm., 2004, 95, 83. 2. The Merck Index, An Encyclopedia of Chemicals, Drugs, and Biological, Fourteenth Ed. Merck Research Laboratories. 2006. The compound was first observed by Scheele in 1786 and prepared by Braconot in 1818.



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3. (a) Park, W. H.; Han, Y. H.; Kim, S. H.; Kim, S. Z., Toxicology, 2007, 235, 130. (b) Han, Y. H.; Kim, S. Z.; Kim, S. H.; Park, W. H., Int. J. Mol. Med., 2008, 21, 721. 4. Yang, C.-J.; Wang, C.-S.; Hung, J.-Y.; Huang, H.-W.; Chia, Y.-C.; Wang, P.-H.; Weng, C.-F.; Huang, M.-S., Lung Cancer, 2009, 66, 162. 5. Gier, H.; Roth W.; Schumm, S.; Gerhards, M.; J. Mol. Struct., 2002, 610, 1. 6. (a) Vishweshwar, P.; Nangia, A.; Lynch, V. M., Chem Commun., 2001, 179. (b) Thallapally, P. K.; Katz, A. K.; Carrell, Desiraju, G. R., Chem Commun., 2002, 344. (c) L. R. MacGillivary; Atwood, J. L., Nature, 1997, 389, 489. (d) Jeffrey, G. A. An Introduction to Hydrogen Bonding, Oxford University Press: New York, 1997. 7. Becker, P.; Brusset, H.; Gillier-Pandraud, H.; C. R. Acad. Sci., Ser. C (Chim), 1972, 274, 1043. 8. (a) Brock, C. P.; Duncan, L. C., Chem. Mater., 1994, 6, 1307. (b) Steiner, T. Acta Crystallogr. 2000, B56, 673. (c) Steed, J. W. CrystEngComm, 2003, 5, 169. 9. Shan, N.; Toda, F.; Jones, W. Chem. Commun., 2002, 2372. 10. Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang, N.-L. Angew. Chem., Int. Ed. Engl., 1995, 34, 1555. 11. Schultheiss, N.; Newman, A. Cryst. Growth Des., 2009, 9, 2950. 12. Fabián, L.; Hamill, N.; Eccles, K. S.; Moynihan, H. A.; Maguire, A. R.; McCausland, L.; Lawrence, S. E. Cryst. Growth Des., 2011, 11, 3522. 13. Good, D. J.; Rodríguez-Hornedo, N. Cryst. Growth Des., 2009, 9, 2252. 14. (a) Thakuria, R.; Nangia, A. CrystEngComm, 2011, 13, 1759. (b) Jayasankar, A.; Reddy, L. S.; Bethune, S. J.; Rodríguez-Hornedo, N. Cryst. Growth Des., 2009, 9, 889. 15. Nangia, A. Acc. Chem. Res., 2008, 41, 595. 16. Cambridge Structural Database, ver. 5.33, ConQuest 1.14, November 2011 release, Feb 2012 update; www.ccdc.cam.ac.uk. 17. Sanphui, P.; Goud, N. R.; Khandavilli, U. B. R., Nangia, A. Cryst. Growth Des., 2011, 11, 4135. 18. van Eijck, B. P.; Kroon, J. Acta Crystallogr. 2000, B56, 535. 19. Anderson, K. M.; Probert, M. R.; Whiteley, C. N.; Rowland, A. M., Goeta, A. E.; Steed, J. W. Cryst. Growth Des., 2009, 9, 1082. 20. http://www.dur.ac.uk/zprime/ and references therein. 21. Brock, C. P.; Minton, R. P. J. Am. Chem. Soc., 1989, 111, 4586. 22. (a) Desiraju, G. R. CrystEngComm, 2007, 9, 91. (b) Das, D.; Banerjee, R.; Mondal, R.; Howard, J. A. K.; Boese, R.; Desiraju, G. R. Chem. Commun., 2006, 555. 23. Glomme, A.; März, J.; Dressman, J. B. J. Pharm. Sci., 2005, 94, 1. 24. Yu, L. X.; Carlin, A. S.; Amidon, G. L.; Hussain, A. S. Int. J. Pharm., 2004, 270, 221.


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TOC

High Z' crystal structures of pyrogallol containing different OH hydrogen bonding conformations are analyzed for the first time. Aqueous slurry experiments indicate form stability of multiple Z' pyrogallol–pyridine-N-coformer cocrystals.


Crystal Structures of Pyrogallol, Its Hydrate, and ... - ACS Publications

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