New Polymorphs of Fluconazole: Results from Cocrystallization

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New Polymorphs of Fluconazole: Results from Cocrystallization Experiments Maheswararao Karanam, Sagarika Dev, and Angshuman Roy Choudhury* Indian Institute of Science Education and Research, Mohali, Sector 81, S. A. S. Nagar, Manauli PO, Punjab, India 140306

bS Supporting Information ABSTRACT: Fluconazole is known as an antifungal drug since 1983. Its propensity for the formation of new polymorphs and salts has been reported in the literature, mostly by powder X-ray diffraction and solid state Raman spectroscopy. In the present study, we are elucidating the structures of four polymorphs of fluconazole using single crystal X-ray diffraction. Raman spectra of the single crystals of these polymorphs also support our study. These polymorphs were grown in the presence of the cocrystal formers. This indicates that fluconazole interacts with the cocrystal former in the solution, and possibly these interactions result into the generation of new polymorphs of it. These polymorphs of fluconazole exhibit the conformational flexibility of the molecule, and hence we observed seven different conformers of the molecule in the reported polymorphs. Although these forms have strong OH 3 3 3 N hydrogen bonds, the nature of the packing of the molecules is a cumulative effect of a number of weaker intermolecular forces such as CH 3 3 3 O, CH 3 3 3 N, and CH 3 3 3 F and the strong hydrogen bond.

’ INTRODUCTION Fluconazole (Scheme 1) [2-(2,4-difluorophenyl)-1,3-di(1H1,2,4-triazol-1-yl)propan-2-ol] is known as an antifungal drug since 1983 from a patent by Richardson.1 This particular compound was first synthesized and reported in the scientific literature by Richardson et al. as the outcome of their research initiated in 1970. 2 Since its introduction by Pfizer in the pharmaceutical industry, a large number of research groups have been engaged in various investigations aiming to generate new polymorphs of fluconazole to enhance its biomedical application. Their efforts have resulted in the generation of number of polymorphs, solvates, and salts of fluconazole, although many of them have been characterized by powder X-ray diffraction (PXRD) data, solid state Raman spectra, and differential scanning calorimetry (DSC) but not by single crystal X-ray diffraction (SCXRD). Lo et al. in their UK patent reported the existence of a monohydrate using SCXRD data in 1994; however, the crystallographic information file (CIF) and information about the unit cell dimensions were not reported. They reported the 2θ and relative intensity data derived from the PXRD data in Table 1 of the patent.3 We would hereafter refer to this as the monohydrate 1 of fluconazole. They have also reported the peak positions from another powder diffraction data (pattern not reported) for an anhydrous from, hereafter referred to as the polymorph 1 of anhydrous fluconazole in the Table 2 of the patent. In 1995, Gu and Jiang reported two polymorphs (identified by them as “polymorphic form-I” and “polymorphic form-II”) of fluconazole using PXRD, solid state Raman spectra, and DSC.4 We observe that the “form I” reported by Gu and Jiang is different from the anhydrous form (polymorph 1) reported by Lo et al., and r 2011 American Chemical Society

hence it is a new form, hereafter referred to as polymorph 2. They also reported that their “form II” was a 1:9 mixture of their “form I” and a new form. On careful investigation of the patterns reported by Gu and Jiang, we realized that the major component of their “form II” is similar to the anhydrous form (polymorph 1) reported by Lo et al. Dash and Elmquist, in their exhaustive description of fluconazole, reported the existence of three forms (termed as “form I”, “form II”, and “form III”) and a monohydrate of fluconazole.5 We observe that their “form I” has peaks, which match with the2θ values and relative intensities of the peaks observed in their “form III” along with some peaks which are matching with the peaks observed in the monohydrate reported by the same authors. Hence we suspect their “form I” was not a pure phase, but it was a mixture of two or more phases. The “form II” reported by Dash and Elmquist is the same as the “form I” reported by Gu and Jiang, that is, polymorph 2 of fluconazole. The “form III”, reported by Dash and Elmquist, was found to be the same as polymorph 1 (Lo et al.). Interestingly, the monohydrate reported by Dash and Elmquist did not match with the data given for the monohydrate 1 by Lo et al. Hence we refer to this monohydrate as monohydrate 2. Alkhamis et al.6 in 2002 illustrated two more anhydrous forms (“form-I” and “form-II”), two solvates, a monohydrate, and an amorphous form of fluconazole using the same techniques used by Gu and Jiang. Alkhamis et al. inferred that their “form-I” was same as the “form-I” reported by Gu and Jiang. Hence this form also will be referred Received: August 3, 2011 Revised: October 31, 2011 Published: October 31, 2011 240

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to as polymorph 2 in this manuscript. Their “form-II” was believed to be a new metastable form, different from the “form-II” reported by Gu and Jiang. This form will hereafter be referred to as polymorph 3 of fluconazole as it was distinctly different from the forms reported earlier. Kreidl et al. in their patents claimed to have generated two more new crystal modifications of fluconazole.7 But we realized that their “crystal modification I” is the same (based on 2θ, d-value, and relative intensity data given in the two patents) as the monohydrate reported by Lo et al., and the “crystal modification II” by Kreidl et al. was significantly similar to the data reported in Table 2 of the patent by Lo et al. Hence, we suspected that “crystal modification I” of Kreidl et al. may be a monohydrate, same as the monohydrate 1 reported by Lo et al., and their “crystal modification II” was the same as polymorph 1 (Lo et al.). Caira et al. for the first time reported SCXRD data of an anhydrous form (CSD refcode IVUQOF), a monohydrate (CSD refcode IVUQIZ), and an ethyl acetate solvate of fluconazole (Table 1) in 2004.8 The anhydrous IVUQOF is observed to be the same anhydrous polymorph reported by Lo et al. (polymorph 1) and

the major component of the “form II” reported by Gu and Jiang. Further, the monohydrate IVUQIZ is different from the monohydrate 1 reported by Lo et al. but is the same as the monohydrate 2 reported by Dash and Elmquist. These literature studies have been tabulated in Supporting Information. These preliminary results have indicated that fluconazole is a very important molecule in the pharmaceutical industry and has potential to form several polymorphs, salts, and solvates. In the last two decades, with the advancements in crystal engineering techniques9 and an increasing interest in the investigations to form cocrystals and salts of the existing active pharmaceutical ingredients (APIs),10 a significant number of research publications from various groups have indicated that the physicochemical properties of the APIs can be altered by the formation of suitable cocrystals or salts. A number of research groups have been interested in generating new salts and cocrystals of fluconazole. McMahon et al. in their patent reported the formation of fluconazole maleate-maleic acid (Table 1) salt in 2006.11 Kastelic et al. reported three cocrystals of fluconazole with three dibasic acids (maleic acid, fumaric acid, and glutaric acid) (Table 1).12 A recent publication reported the formation of a cocrystal of fluconazole with salicylic acid (Table 1).13 All these new cocrystals, the anhydrous polymorph 1, monohydrate, and ethyl acetate solvate were found to have OH 3 3 3 N hydrogen bonded molecular chain or dimer of fluconazole molecules. We initiated our experiments of growing cocrystals and salts of this compound with the possibility of formation of various polymorphs, salts, and cocrystals of fluconazole with pharmaceutically acceptable cocrystal formers. Fluconazole, being a very weak base (pKa = 1.76 for it conjugate acid),14 it was expected that very strong organic acids may form salts with it and weak organic acids may form cocrystals.1517 We have used saccharin (pKa = 2),18 benzoic acid (pKa = 4.19), salicylic acid (pKa = 2.98, 13.82),18

Scheme 1. Structure of Fluconazole

Table 1. List of Crystal Structures of Anhydrous Form of Fluconazole, Solvates, Salts, and Cocrystals fluconazole anhydrous form8

fluconazole monohydrate8

fluconazole ethylacetate solvate8

fluconazole cocrystal with maleic acid11

crystal system sp gr

triclinic P1

triclinic P1

monoclinic P21/c

monoclinic C2

a (Å)

7.4992(1)

5.6258(1)

6.0484(1)

36.557(6)

b (Å)

7.7869(1)

11.7373(2)

38.5004(6)

5.695(6)

c (Å)

11.9817(2)

12.3063(3)

12.9698(2)

12.771(7)

α ()

84.947(1)

71.235(1)

90.0

90.0

β ()

84.625(1)

79.871(1)

90.222(1)

94.530

γ ()

75.894(1)

84.383(1)

90.0

90.0

V (Å3) Z

674.05(2) 2

756.68(3) 2

3020.20(8) 8

2650.52 4

fluconazole cocrystal with maleic

fluconazole cocrystal with fumaric

fluconazole cocrystal with glutaric

fluconazole cocrystals with salicylic

acid12

acid12

acid12

acid13

crystal system

triclinic

triclinic

triclinic

triclinic

sp gr

P1

P1

P1

P1

a (Å)

5.49830(10)

8.4151(3)Å

5.6897(2)

6.8522(2)

b (Å)

13.8723(4)

10.0035(4

10.6590(3)

10.5580(4)

c (Å) α ()

18.4331(5) 98.0620(10)

10.6165(3) 75.077(2)o

17.0635(5) 72.909(2)

14.3009(6) 82.862(3)

β ()

91.748(2)

86.219(3)o

84.453(2)

84.892(2)

γ ()

95.479(2)

76.054(2)o

80.863(2)

86.091(3)

V (Å3)

1384.34(7)

838.10(5)

975.22(5)

1020.80(6)

Z

2

2

2

2

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phthalic acid (pKa = 2.98, 5.28), L-glutamine (pKa = 2.17, 9.13), and glycolic acid (pKa = 3.82)18 (Scheme 2) to form a cocrystal/salt with fluconazole. We have identified four polymorphs (referred to as then polymorph 4, polymorph 5, polymorph 6, and polymorph 7) and two salts of fluconazole with oxalic acid in these experiments. We shall elucidate the structures of the polymorphic modifications of fluconazole and will not include the salts in this manuscript. This phenomenon of generating new polymorphs as a result of the cocrystallization experiment had been documented in earlier literature. 19 Table 2 lists the conditions and cocrystal formers, which yielded these new polymorphs. In the present study, we are elucidating the crystal structures and intermolecular interactions observed in these new forms of fluconazole using single crystal X-ray diffraction, solid state Raman spectroscopy, theoretical calculation of single point stabilization energy, and geometry optimization.

Cocrystallization Experiments. Fluconazole was mixed with one of the cocrystal formers (saccharin, benzoic acid, salicylic acid, phthalic acid, L-glutamine, glycolic acid, and oxalic acid dihydrate) either in a 1:1, 1:2, and 2:1 molar ratio, and the mixtures were dissolved in different solvents and solvent mixtures at room temperature (RT) (2225 C) in 5 mL beakers. These beakers were then covered with paraffin film and a few small holes were made using a needle to allow the solvent to evaporate slowly at 4 C in a refrigerator. The complete details of the cocrystallization experiments and screening of the cocrystallization residues using optical microscopy and powder X-ray diffraction are included in the Supporting Information (Table S1 and Figures S228). Computational Studies. Gas phase geometry optimizations and single point energy calculations have been carried out at the HartreeFock level (HF) with 6-31 g* basis set using Gaussian 0320 suite of programs on all the seven different conformers encountered in the four new polymorphs. Vibrational frequency analysis at the same level with the same basis set ensures that the optimized geometries correspond to true minima. Stabilization energy (ΔEs = Eopt ∑Eelemental) of each of the optimized conformer was computed as the difference between the energy of the conformer and that of the constituting elements. Screening and Characterization. After complete evaporation of the solvent, the products in each of the crystallization beakers were carefully examined under an optical polarizing stereo microscope (Olympus SZX10 equipped with DF PLAPO 1.25 objective lens, WHSZ10X-H eyepiece and a Venus USB 2.0 Camera). The details of crystallization experiments and microscopic observations are listed in Table 1 of Supporting Information for all the experiments. The single crystals obtained in these experiments were analyzed by single crystal X-ray diffraction (unit cell determination only). The observations from these cell determination exercises are also listed in in Table 1 of Supporting Information. Single crystal X-ray diffraction experiments were carried out on a Bruker AXS KAPPA APEX-II CCD diffractometer (Monochromatic Mo Kα radiation) equipped with Oxford cryosystem 700Plus. Data collection and unit cell refinement for the data sets were done using the Bruker APEX-II21 suite, data reduction and integration were performed by SAINT V7.685A21 (Bruker AXS, 2009), and absorption corrections and scaling were done using SADABS V2008/121 (Bruker AXS). The crystal structures were solved by using Olex222 or WinGx23 packages using SHELXS9724 and the structures were refined using SHELXL97.24 Single crystal data and refinement results are listed in Table 3. All the figures including the packing and interaction diagrams were generated using Mercury.25 Geometric calculations including the least-squares plane angles were done using PARST.26 The products of crystallization beakers, which did not produce suitable single crystals, but resulted in polycrystalline powder, were studied using PXRD. PXRD data were recorded on a Rigaku Ultimia IV diffractometer using parallel beam geometry equipped with a Cu Kα source, 2.5 primary and secondary solar slits, 0.5 divergence slit with 10 mm height limit slit, sample rotation stage (120 rpm) attachment

’ EXPERIMENTAL SECTION Starting Materials. A sample of fluconazole was obtained from Hikal India Ltd., Bangalore, India. This sample was identified as monohydrate by PXRD (Supporting Information, Figure S1), and it corresponds to the monohydrate 1 reported by Caira et al.7 Saccharin and phthalic acid were obtained from Sigma-Aldrich, glycolic acid and L-glutamine were obtained from Spectrochem Pvt. Ltd., India, and oxalic acid dihydrate, salicylic acid, and benzoic acid were obtained from Merck. Analytical grade solvents were obtained from Sisco Research Laboratories Pvt. Ltd., India. All the starting materials including fluconazole were used without further purification for crystallization experiments.

Scheme 2. Structures of Cocrystal Formers Used in This Study

Table 2. Cocrystal Formers Used and Conditions That Resulted into Four New Polymorphs and Two New Salts of Fluconazole name of the cocrystal former saccharin

pKa value(s)

mole ratios

solvent system and growth conditions

results

2.0

1:1

methanol, 4 C

polymorph 4

1:1

acetonitrile, 4 C

polymorph 6

benzoic acid

4.19

2:1

acetonitrile +1 drop of water, RT

polymorph 7

salicylic acid

2.98, 13.82

2:1

ethanol, 4 C

polymorph 4 and polymorph 7

phthalic acid L-glutamine

2.98, 5.28 2.17, 9.13

1:2 1:1

acetonitrile, 4 C acetone + water (50:50), RT

polymorph 6 polymorph 7

glycolic acid

3.82

1:1

acetonitrile, 4 C

polymorph 5

1:1

methanol + water, RT

polymorph 7

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Table 3. Crystallographic Data and Structure Refinement Parameters of Fluconazole Polymorphic Forms identification code

polymorph 4

polymorph 5

polymorph 6

polymorph 7

CCDC depository number

816585

816586

816587

816588

empirical formula

C13H12F2N6O

C13H12F2N6O

C13H12F2N6O

C13H12F2N6O

formula weight

306.3

306.3

306.3

306.3

crystal size (mm)

0.3 0.2 0.1

0.1 0.2 0.1

0.2 0.2 0.1

0.1 0.3 0.1

crystal system

monoclinic

orthorhombic

monoclinic

orthorhombic

space group

P21/n

Pbca

C2/c

Pbca

a (Å)

6.6985(4)

12.9282(9)

27.4726(9)

10.9186(9)

b (Å) c (Å)

27.3858(19) 15.2898(11)

6.0241(5) 34.834(3)

10.9196(4) 22.3424(12)

22.3367(18) 22.3619(17)

α ()

90.0

90.0

90.0

90.0

β ()

90.319(3)

90.0

125.337(2)

90.0

γ ()

90.0

90.0

90.0

90.0

V (Å3)

2804.8(3)

2712.9(4)

5467.6(4)

5453.74(8)

Z

8

8

16

16

Z0

2

1

2

2

Fcalc (g cm3) temperature (K)

1.451 100.0(1)

1.500 100.0(1)

1.488 100.0(1)

1.497 100.0(1)

μ (mm1)

0.117

0.121

0.120

0.120

theta ranges for data collection (o)

1.5322.55

1.1725.82

2.0725.35

1.8225.03

F(000)

1264

1264

2528

2528

index ranges

7 e h e 7

15 e h e 13

32 e h e 30

5 e h e 12

29 e k e 29

7 e k e 6

11 e k e 13

26 e k e 26

16 e l e16

42 e l e 36

26 e l e 25

26 e l e 26

no. of reflections collected Rint

36329 0.0522

13086 0.0449

17333 0.0407

35205 0.0534

no. of unique reflections

3666

2612

4968

4798

no. of parameters

493

240

493

399

R1 [I > 2σ(I)]

0.0346

0.0696

0.0649

0.0861

wR2 (all data)

0.0822

0.1665

0.2002

0.2650

GOF

1.024

1.158

1.065

1.066

largest diff peak/hole (e Å3)

0.125/0.196

0.277/0.340

0.598/0.289

1.057/0.436

and DTex Ulta detector. The X-ray generator was operated at 40 kV and 40 mA power settings. The data were collected over an angle range 560 with a scanning speed of 5 per minute with 0.02 step. The single crystals of the new polymorphs of fluconazole were also studied using Raman spectroscopy. Raman spectra were recorded on Renishaw InVia Raman microscope equipped with 785 nm high-power near-infrared laser working at 300 mW power and a Renishaw CCD detector. Analysis were performed in reflection mode on single crystal mounted on glass fiber placed on sample stage and aligned in optical path by using camera, with 1050% laser power and by using 2050 optics in the range of 2004000 cm1. The crystals of these four polymorphs (47) were used to seed saturated solutions of fluconazole in the same solvent systems but without the respective cocrystal former. All such experiments resulted into the monohydrate7 of fluconazole, and none of them reproduced the same polymorph, which was used to seed. In contrast, these forms could be reproduced several times when the same solvent systems and the same proportions of the cocrystal formers were used. It was observed that the crystals of the new polymorphs of fluconazole were grown on the surface of the crystalline lump of the cocrystal former (Figure 1). This perhaps indicates that the appearances of those new polymorphs are the result of the interactions between fluconazole molecules present in the solution and the crystal of the cocrystal former. Interestingly, these anticipated interactions between the

Figure 1. Photograph of the crystal habit of the polymorph 7 of fluconazole. fluconazole molecule and the cocrystal former did not yield any cocrystal or salt in those combinations. 243



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Scheme 3. Fluconazole Molecules with Atoms, Rings (R), and Molecule Numbering

Table 4. List of Selected Torsion Angles in Fluconazole Molecules (Seven Conformers in Four Polymorphs) atoms used in measuring the torsion angle

4A and 4B of polymorph 4

polymorph 5



C3C2C1O1

C16C15C14-O2

169.17; 172.35

179.82

177.19; 175.94

175.05; 179.75

C1C8N1N2 C1C11N4N5

C14C21N7N8 C14C24N10N11

79.33; 83.98 91.9; 77.04

73.26 90.35

84.91; 83.34 81.13; 92.28

84.14; 79.78 90.58; 86.91

C1C8N1C10

C14C21N7C23

101.86; 92.69

104.22

95.20; 96.78

95.88; 97.05

C1C11N4C13

C14C24N10C26

88.99; 102.34

90.41

95.87; 87.61

88.67; 95.80

C2C1C8N1

C15C14C21N7

65.38; 55.58

68.35

167.15; 66.22

64.80; 69.16

C2C1C11N4

C15C14C24N10

65.21; 64.53

174.96

68.31; 176.97

178.59; 167.21

Figure 2. (a) Molecular overlay of 4A (green) and 4B (yellow), (b) infinite chain formation along the b-axis maintaining 21-screw symmetry by using OH 3 3 3 N hydrogen bonds, (c) overall packing of unit cell including CH 3 3 3 F and CH 3 3 3 N interactions, viewed along the a-axis, (d) dimer formation in asymmetric unit, (e) dimers involving H 3 3 3 F interactions, (f) CH 3 3 3 N hydrogen polymorph 4.

’ RESULTS

The same numbering scheme has been followed for all the polymorphs reported in this manuscript. The conformations of these two molecules are different in terms of a few torsion angles (Table 4), and the molecular overlay is shown in Figure 2a [4A (green) and 4B (yellow)]. The molecules 4A and 4B are connected to each other by strong OH 3 3 3 N hydrogen bonds forming infinite chains along b-axis maintaining 21-screw symmetry

Crystal Structure of Polymorph 4 of Fluconazole. This polymorph was found to crystallize in the centrosymmetric monoclinic P21/n space group with two molecules (molecule 1 = 4A and molecule 2 = 4B) in the asymmetric unit. The atom numbering scheme for these molecules are shown in Scheme 3. 244



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Table 5. Intermolecular Interactions in Polymorph 4 of Fluconazole

a

DH 3 3 3 A

D (D 3 3 3 A)/Å

d (H 3 3 3 A)/Å

— DH 3 3 3 A/

O2H2 3 3 3 N3 O1H1 3 3 3 N9 C26H26 3 3 3 O1

2.783(3)

1.87(3)

171(3)

x + 1/2, y + 1/2, z+ 1/2

2.824(3)

1.92(3)

177(3)

x + 1/2, y + 1/2, z 1/2

3.208(4)

2.29(3)

164(2)

x, y, za

C13H13 3 3 3 O2 C11H11A 3 3 3 O2

3.207(3)

2.40(3)

143(2)

x, y, za

3.475(3)

2.60(3)

146(2)

x, y, za

C23H23 3 3 3 N6 C22H22 3 3 3 F2 C17H17 3 3 3 N11 C25H25 3 3 3 N5

symmetry

3.297(4)

2.46(3)

148(2)

x 1, y, z

3.219(4)

2.55(3)

127(2)

x 1/2, y + 1/2, z + 1/2

3.540(4) 3.272(4)

2.67(4) 2.69(3)

157(3) 121(2)

x, y + 1/2, z x + 1/2, y + 1/2, z 1/2

These are actually intermolecular interactions between the two molecules present in the asymmetric unit.

Figure 3. (a) Intramolecular CH 3 3 3 F hydrogen bonds, (b) OH 3 3 3 N hydrogen bonded chains, (c) CH 3 3 3 O and CH 3 3 3 N hydrogen bonded chains, (d) overall packing in polymorph 5.

(Figure 2b). The two molecules in the asymmetric unit form a dimer involving two different CH 3 3 3 O (C11H11B 3 3 3 O2, C13H13 3 3 3 O2 and C26H26 3 3 3 O1) hydrogen bonds (Figure 2c). Table 4 suggests that these two molecules have different conformations with respect to the orientation of the phenyl ring and the two triazole rings. The overall packing is shown in the Figure 2d. Two 4A molecules form a dimer involving F2 3 3 3 H9 atoms and two 4B molecules are also connected to this dimer involving CH 3 3 3 F interaction through F2 of 4A molecule and H22 of 4B molecule (Figure 2e). Further, two 4B molecules form a dimer involving C17H17 3 3 3 N11 hydrogen bond. A pair of this dimer is connected to each other through another 4A molecule involving two CH 3 3 3 N hydrogen bonds (C23H23 3 3 3 N6, C25H25 3 3 3 N5) (Figure 1f). All these interactions are listed

in Table 5. The simulated PXRD pattern of this polymorph was compared with the PXRD patterns reported earlier for polymorphs 13, and we note that this is a new polymorph of fluconazole, referred to as polymorph 4. Crystal Structure of Polymorph 5 of Fluconazole. This form crystallizes in the centrosymmetric orthorhombic Pbca space group with one molecule (molecule 1 = 5A) in the asymmetric unit. The molecular conformation is different from the conformers observed in other polymorphs in terms of torsion angles and least-squares plane angles (Table 4). Two intramolecular CH 3 3 3 F hydrogen bonds involving two CH2 groups in the molecule are responsible for this particular molecular conformation in this polymorph (Figure 3a). This form of fluconazole has been found to form infinite chains (Figure 3b) using the O1H1 3 3 3 N3 hydrogen bond along the a-axis and a 245



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Table 6. Intermolecular Interactions in Polymorph 5 of Fluconazole DH 3 3 3 A O1H1 3 3 3 N3 C12H12 3 3 3 O1

D (D 3 3 3 A)/Å

d (H 3 3 3 A)/Å

— DH 3 3 3 A/

symmetry

2.745(3)

1.94(1)

166(1)

x + 1/2 + 1, +y + 1/2, z

3.448(5)

2.64(4)

142(3)

x + 1, y 1/2, z + 1/2

C10H10 3 3 3 N6 C8H8A 3 3 3 N5

3.293(5)

2.55(1)

137(2)

x + 1, y 1/2, z + 1/2

3.197(5)

2.55(3)

125(2)

x, y, z

C8H8B 3 3 3 F1 C11H11A 3 3 3 F1

2.970(4)

2.32(4)

125(3)

x, y, z

3.059(4)

2.47(3)

123(3)

x, y, z

Figure 4. (a) Overlap of 6A and 6B molecules, (b) intramolecular CH 3 3 3 F interaction, (c) dimers of 6A and 6B, (d) chain of dimers involving CH 3 3 3 F and CH 3 3 3 N hydrogen bonds, (e) crystal packing of fluconazole polymorph 6 viewed along the b-axis.

Table 7. Intermolecular Interactions in Polymorph 6 of Fluconazole DH 3 3 3 A

d (H 3 3 3 A)/Å

— DH 3 3 3 A/

symmetry

2.879(4)

2.06(5)

173(5)

x, y, z + 1/2 + 1

2.860(3) 3.246(8)

2.07(4) 2.41(6)

170(5) 144(4)

x, y, z + 1/2 x + 1/2, y 1/2, z + 1

C17H17 3 3 3 N12 C4H4 3 3 3 N6

3.318(4)

2.42(3)

156(3)

x, y 1, z

3.274(5)

2.45(4)

144(3)

x, y + 1, z

C22H22 3 3 3 N2 C21H21B 3 3 3 N11

3.491(4)

2.50(4)

167(3)

x, y + 1, z + 1/2

3.160(5)

2.52(4)

122(3)

x, y, z

3.229(4)

2.57(3)

124(2)

x, y, z

O2H2 3 3 3 N9 O1H1 3 3 3 N3 C12H12 3 3 3 N5

a

D (D 3 3 3 A)/Å

C8H8A 3 3 3 N5 C10H10 3 3 3 N8 C21H21A 3 3 3 F3 C13H13 3 3 3 F4

3.502(4)

2.58(4)

165(3)

x, y, z 1/2

2.952(5) 3.257(7)

2.27(4) 2.28(8)

122(3) 158(6)

x, y, z x, y, za

C8H8B 3 3 3 F1 C6H6 3 3 3 F2

2.972(4)

2.33(3)

123(2)

x, y, z

3.360(6)

2.49(5)

154(4)

x, y + 1, -z + 1

3.428(5)

2.53(4)

155(3)

x, -y, -z+1

3.468(3)

2.56(3)

155(3)

x, -y+1, -z+1

C7H7 3 3 3 F4 C20H20 3 3 3 F2

These are actually intermolecular interactions between the two molecules present in the asymmetric unit.

π-stacking of triazole rings along the b-axis with a distance of 3.083 Å between the two triazole rings. These infinite chains are

related by the center of symmetry. Further, the fluconazole molecules have been found to form another chain involving 246



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Figure 5. (a) Overlap of 7A and 7B, (b) 7A 3 3 3 7B dimers by involving OH 3 3 3 N strong hydrogen bonds, (c) dimer involving CH 3 3 3 F hydrogen bonds, (d) 7A forming infinite chains of dimers, (e) 7A and 7B forming infinite chains in polymorph 7.

CH 3 3 3 O and CH 3 3 3 N hydrogen bonds (Figure 3c). Interestingly, no intermolecular CH 3 3 3 F interactions are observed in this polymorph. Figure 3d shows overall packing of molecules with all these interactions marked as dotted lines, and these interactions are listed in Table 6. It is interesting to note that the simulated PXRD of this polymorph has significant similarity to the “crystal modification I” reported by Kreidl et al., but the PXRD data (2θ, d-values, and rel intensity) given in the patent by Kreidl et al. is identical to the PXRD data given for the monohydrate in the patent by Lo et al. As we have not found the presence of any water molecule in our single crystal structure solution and refinement and as there is no significant unassigned electron density in our refinement, we conclude that the monohydrate reported by Lo et al. is actually an anhydrous form (same as “crystal modification I” reported by Kreidl et al.) of fluconazole. We would hereafter refer to this form as polymorph 5.

Crystal Structure Polymorph 6 of Fluconazole. This polymorph crystallizes in the centrosymmetric monoclinic C2/c space group with two molecules (molecule 1 = 6A and molecule 2 = 6B) in the asymmetric unit. These two molecules differ in their torsion angles (Table 4), and the overlap of 6A (green) and 6B (yellow) is shown in Figure 4a. Both 6A and 6B molecules have intramolecular CH 3 3 3 F interactions involving the CH2 groups in the molecule. These intramolecular interactions lock the conformation of the molecule (Figure 4b) similar to polymorph 5. These two molecules (6A and 6B) have been found to form dimers like 6A 3 3 3 6A and 6B 3 3 3 6B fashion by involving OH 3 3 3 N hydrogen bonds (Figure 4c). The 6A and 6B molecules have been found to form a chain of dimers involving CH 3 3 3 F and CH 3 3 3 N hydrogen bonds (Figure 4d). The overall packing diagram is shown in Figure 4e. All these interactions are listed in Table 7. It is noteworthy that this particular form does not have any 247



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Table 8. Intermolecular Interactions in Polymorph 7 of Fluconazole DH 3 3 3 A O2H2 3 3 3 N3 O1H1 3 3 3 N9 C4H4 3 3 3 N6 C25H25 3 3 3 N11 C8H8B 3 3 3 N5

D (D 3 3 3 A)/Å

d (H 3 3 3 A)/Å

— DH 3 3 3 A/

symmetry

2.849(4)

2.02(3)

166.9(2)

x 1, y, z

2.885(4)

2.05(3)

173.9(2)

x + 1, y, z x 1, y, z

3.298(5)

2.43(4)

151.6(2)

3.274(6)

2.46(4)

144.2(3)

x, y + 1, z + 2

3.160(5)

2.53(4)

120.9(2)

x, y, z

3.322(6)

2.53(4)

140.9(2)

x 1, y, z

3.263(5)

2.57(4)

126.8(2)

x, y, z

3.480(5) 3.523(5)

2.58(3) 2.60(3)

157.8(2) 164.8(2)

x + 1/2 + 1, y, z + 1/2 + 1 x 1/2, y, z + 1/2 + 1

C8H8A 3 3 3 F1 C21H21B 3 3 3 F3

2.940(4)

2.26(2)

124.7(2)

x, y, z

2.984(4)

2.30(3)

125.7(2)

x, y, z

C26H26 3 3 3 F2 C24H24A 3 3 3 F3

3.261(6)

2.36(2)

158.7(3)

x, y + 1/2, z + 1/2 + 1

3.108(5)

2.52(2)

118.0(2)

x, y, z

C17H17 3 3 3 N12 C21H21A 3 3 3 N11 C10H10 3 3 3 N8 C23H23 3 3 3 N2

C11H11B 3 3 3 F1 C7H7 3 3 3 F2 C20H20 3 3 3 F4 C6H6 3 3 3 F4

3.151(5)

2.53(3)

120.7(2)

x, y, z

3.445(5)

2.53(2)

160.7(2)

x + 1/2, y, z + 1/2 + 1

3.447(5) 3.437(5)

2.55(2) 2.56(3)

156.9(2) 154.2(2)

x + 1/2, y, z + 1/2 + 1 x 1/2, y 1/2, z

Table 9. List of Selected Torsion Angles for Optimized Geometries

CH 3 3 3 O hydrogen bond in the packing. We have compared the simulated PXRD pattern of this polymorph with the PXRD data available for polymorphs 13, and we observed that this is also a new polymorph, referred to as polymorph 6 of anhydrous fluconazole. Crystal Structure of Polymorph 7 of Fluconazole. This polymorph crystallizes in the centrosymmetric orthorhombic Pbca space group with two molecules (molecule 1 = 7A and molecule 2 = 7B) in the asymmetric unit. These two molecules differ in their torsion (Table 4). The molecular overlap of 7A and 7B is shown in the Figure 5a. The molecules 7A (green) and 7B (yellow) form 7A 3 3 3 7B dimers by involving strong OH 3 3 3 N hydrogen bonds in the unit cell (Figure 5b) in contrast to 6A 3 3 3 6A and 6B 3 3 3 6B dimers in polymorph 6 (Figure 4c). Each 7A 3 3 3 7B dimer is further connected to other 7A 3 3 3 7B dimers involving CH 3 3 3 N hydrogen bonds (Figure 5b). Figure 5c shows the molecular chains of the type 3 3 3 7A 3 3 3 7A 3 3 3 7A 3 3 3 and 3 3 3 7B 3 3 3 7B 3 3 3 7B 3 3 3 formed by weak CH 3 3 3 F interactions. These two antiparallel chains of 7A and 7B molecules are connected to each other by another set of CH 3 3 3 F interactions (Figure 5c). Further, two 7B molecules are found to form a dimer involving CH 3 3 3 N hydrogen bonds, and these dimers form a chain involving another pair of CH 3 3 3 N hydrogen bonds (Figure 5d). Further, molecular chains of the type 3 3 3 7A 3 3 3 7A 3 3 3 7A 3 3 3 and 3 3 3 7B 3 3 3 7B 3 3 3 7B 3 3 3 are observed in the packing involving CH 3 3 3 N hydrogen bonds, and again these chains are interlinked by another set of CH 3 3 3 N hydrogen bonds (Figure 5e). Table 8 lists all these interactions. We have compared the simulated PXRD pattern of this polymorph with the PXRD data available for polymorphs 13 and observed that this is also a new polymorph, referred to as polymorph 7 of anhydrous fluconazole. Theoretical Studies. The theoretical calculations show that the two conformers 4A and 4B of polymorph 4 of fluconazole have converged to a new conformer (Aopt) having new set of torsion angles. Further, it is also interesting to note that the other conformers, namely, 5A, 6A, 6B, 7A and 7B when optimized, yielded another new conformer (Bopt). The torsion

atoms used in measuring the torsion angle

Aopt ()

Bopt ()

176.347

177.426

86.095

79.668

C14C24N10N11

104.801

97.013

C14C21N7C23 C14C24N10C26

95.517 74.144

103.629 81.921

C2C1C8N1

C15C14C21N7

67.701

69.642

C2C1C11N4

C15C14C24N10

54.175

176.899

C3C2C1O1

C16C15C14O2

C1C8N1N2

C14C21N7N8

C1C11N4N5 C1C8N1C10 C1C11N4C13

angles of these two optimized conformations of fluconazole are listed in Table 9. All the torsion angles of Aopt and Bopt are significantly different in the range of 250. Their energies are different by about 2 kcal/mol (Table 10). This indicates that fluconazole has a high tendency to form a number of conformers in the gas phase. These different stable conformers, observed in the gas phase, when packed in the form of crystal lattices may lead to the formation of different polymorphs by small changes in the gas phase conformation. Analysis of Raman Spectra. Raman spectra of the four Polymorphs of fluconazole have been recorded and analyzed. Figure 6 displays the Raman spectra of the four new polymorphs and fluconazole monohydrate. The peaks in the Raman spectra of the four polymorphs significantly differ from one another in various ranges of wave numbers as marked in Figure 6. These differences at different ranges of wave numbers indicate that the molecular vibrations (ring stretching, in and out of plane deformations of the triazole and the aromatic ring) are significantly altered by the three-dimensional arrangement (to be precise crystal packing) of fluconazole molecules and the intermolecular forces active on each of the molecules. These Raman spectra of the four forms clearly show the existence of four polymorphs as proved by the single crystal X-ray diffraction data. 248



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Table 10. List of Conformational Energies of the Different Asymmetric Units single point stabilization energy

optimized geometry

optimized geometry stabilization energy

name of the asymmetric unit fragment

single point stabilization energy (kcal/mol)

(kcal/mol), [assuming the most stable conformation (6B) having zero energy]

stabilization energy (kcal/mol)

(kcal/mol) [assuming the most stable conformation (6B) having zero energy]

4A of polymorph 4

3768.1

43.1

3883.5 (Aopt)

72.3

4B of polymorph 4

3776.2

35.0

5A of polymorph 5

3737.8

73.4

3885.4 (Bopt)

74.2

6A of polymorph 6

3789.6

21.6

6B of polymorph 6

3811.2

0.0

7A of polymorph 7 7B of polymorph 7

3793.6 3791.8

17.6 19.4

Figure 6. Raman spectra of the polymorph 4 (black), polymorph 5 (red), polymorph 6 (blue), polymorph 7 (light green), and fluconazole monohydrate (pink).

’ DISCUSSION In our recent efforts to generate new cocrystals of fluconazole, we have found the crystals of four polymorphs of fluconazole and determined their structures using a single crystal X-ray diffraction technique. A careful analysis of the four new polymorphs of fluconazole indicates that three of these polymorphs are new and one polymorph (polymorph 5) is same as one of the polymorphs reported earlier. The new polymorphs reported here could not be made in large amounts by the method of seed crystallization. We have further tried to generate these new polymorphs by using the cocrystal former as an additive, and we have carried out experiments where 520% of the cocrystal former was added with fluconazole using the same solvent. These new polymorphs could not be generated in these additive experiments also. Either a physical mixture of the two compounds or the monohydrate of fluconazole with powder of the cocrystal former was obtained. On the other hand, a 1:1 mixture of fluconazole and the respective cocrystal former always yielded the new polymorphs reported in this manuscript. From these observations, we believe that the interaction between the API and the cocrystal former (1:1) in the solution plays a significant role in the nucleation and growth of the new polymorphs of fluconazole. The formation of the crystals

of the new forms of fluconazole on the crystal lump of the cocrystal former also indicates the possible interaction between the fluconazole molecules in solution and just crystallized coformer present in the solution. As we observe that our polymorph 5 is the same as the crystal modification I reported by Kreidl et al., we tried to reproduce the same crystal modification following procedure 8 and 9 reported in their patents (WO02/076955A1 and US2004/0106804A1). We obtained three different PXRD patterns of fluconazole in these processes but did not get the same crystal modification I reported by Kreidl et al. By following procedure 8 of the patent, using isopropyl alcohol as solvent, we have observed the appearance of a crystalline phase of fluconazole. This pattern was reproducible. Following procedure 9, using ethanol as solvent, we found two different patterns in two trials. TGA (Supporting Information, Figures S3739) and DSC (Supporting Information, Figures S4042) data on these solids indicated that these are nonsolvated polymorphs of fluconazole with melting points of 134.68, 136.29, 138.92 C. We observed that the PXRD (Supporting Information, Figure S43) of the material obtained by recrystallization from isopropanol is significantly similar to the PXRD of the “form II” reported by Alkhamis et al., while the other two PXRD patterns did 249



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Figure 7. Comparison of the PXRD patterns (simulated or recorded) of anhydrous polymorphs of fluconazole and a monohydrate. Patterns for polymorph 1 and monohydrate 2 are simulated from the reported SCXRD data. Patterns for polymorphs 47 are simulated from the SCXRD data reported in this manuscript, and the patterns for polymorphs 8 and 9 are from experimental data.

not match the PXRD patterns reported by any of the earlier reports and the simulated PXRD patterns of the polymorphs reported in this manuscript (Figure 7). We have also found that the melting point and melting feature of the material obtained by recrystallization from isopropanol matched “form II” reported by Alkhamis et al., and hence this form is polymorph 3. The other two materials resulted from ethanol solvent will be hereafter referred to as polymorph 8 and polymorph 9 of fluconazole. The polymorphs 47 should be classified as conformational polymorphs as the molecular conformations are significantly different in all the polymorphs. The four polymorphs reported in this manuscript have the same number (one) of the strong OH 3 3 3 N hydrogen bond per molecule. Polymorphs 4 and 5 have 23 weak intermolecular interactions (CH 3 3 3 O/N/F), and thus the stronger OH 3 3 3 N hydrogen bond directs the chain formation in the lattice. In polymorphs 6 and 7, there are 67 weak intermolecular interactions (CH 3 3 3 O/N/F) per molecule. Their cumulative strength becomes more dominating to alter the overall packing to have OH 3 3 3 N hydrogen bonded dimer rather than chain formation. Hirshfield27 calculations (see Supporting Information) also indicate the same trend.

Polymorphs 4 and 5 do not show any significant contribution of F 3 3 3 H interaction in the plots, while in the plots of polymorph 6 and 7, active contribution of F 3 3 3 H is evident. A similar feature has been observed in the structures of halogenated benzanilidies, where weaker CH 3 3 3 F hydrogen bonds have generated various crystal structures in the presence of the amide group, which is known to form strong hydrogen bonded supramolecular assemblies.28 Because of the unavailability of a large amount (510 mg) of these four polymorphs, thermochemical properties and melting points of these could not be recorded. Attempts are being carried out to generate larger amounts of these polymorphs for their future dissolution, thermochemical and biological activity studies. Gas phase calculations on these new polymorphs show that the molecular stabilization energy of various conformers of fluconazole in the solid state are significantly different (ranging between 3737.8 and 3811.2 kcal/mol), and when their conformations were optimized, they converged to two different conformers which differ in stabilization energy approximately by 2 kcal/mol.

’ CONCLUSION Four polymorphs have been identified in the process of cocrystallization of fluconazole with different cocrystal 250



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formers. The conformational flexibility of the molecule and availability of various hydrogen bond donor and acceptor sites have facilitated the molecule to have different conformers such that the different conformers could recognize the neighboring molecules (fluconazole or coformer) in different ways. We have shown that Raman spectra recorded on single crystals can be used to identify different polymorphs, especially when powder X-ray diffraction data cannot be recorded due to unavailability of a large amount (25 mg) of the material. Our experiments further emphasize the statement “every compound has different polymorphic forms, and that, in general, the number of forms known for a given compound is proportional to the time and money spent in research on that compound” by McCrone 29 regarding the generation of new polymorphs of a compound.

(4) Gu, X. J.; Jiang, W. J. Pharm. Sci. 1995, 84, 1438–1441. (5) Dash, A. K.; Elmquist, W. F. Fluconazole. In Analytical Profiles of Drug Substances and Excipients; Brittain, H. G., Ed.; Academic Press: San Diego, 2001; Vol. 27, pp 67113. (6) Alkhamis, K. A.; Obaidat, A. A.; Nuseirat, A. F. Pharm. Dev. Technol. 2002, 7, 491–503. (7) (a) Kreidl, J.; Czibula, L.; Szantay, C.; Farkas, J.; DeutschneJuchasz, I., Hegedus, I.; Werkne-Papp, E.; Nagyne-Bagdy, J., Piller, A. WO Patent, WO02/076955 A1, 2002. (b) Kreidl, J.; Czibula, L.; Szantay, C.; Farkas, J.; Deutschne-Juchasz, I., Hegedus, I.; Werkne-Papp, E.; NagyneBagdy, J., Piller, A. U.S. Patent, US 007094904 B2, 2006. (8) Caira, M. R.; Alkhamis, K. A.; Obaidat, R. M. J. Pharm. Sci. 2004, 93, 601–611. (9) (a) Desiraju, G. R. Cryst. Growth Des. 2011, 11, 896–898. (b) Desiraju, G. R. Angew. Chem., Int. Ed. 2007, 46, 8342–8356. (c) Desiraju, G. R. J. Mol. Struct. 2003, 656, 5–15. (10) (a) Babu, N. J.; Nangia, A. Cryst. Growth Des. 2011, 11, 2662–2679. (b) Cheney, M. L.; Weyna, D. R.; Shan, N.; Hanna, M.; Wojtas, L.; Zaworotko, M. J. J. Pharm. Sci. 2011, 100, 2172–2181. (c) Vangala, V. R.; Chow, P. S.; Tan, R. B. H. CrystEngComm 2011, 13, 759–762. (d) Shan, N.; Zaworotko, M. J. Drug Discovery Today 2008, 13, 440–446. (e) Oswald, I. D. H.; Motherwell, W. D. S.; Parsons, S.; Pidcock, E.; Pulham, C. R. Crystallogr. Rev. 2004, 10, 57–66. (f) Remenar, J. F.; Morisette, S. L.; Peterson, M. L.; Moulton, € J. Am. Chem. Soc. B.; MacPhee, J. M.; Guzman, H. R.; Almarsson, O. 2003, 125, 8456–8457. (g) Zerkowski, J. A.; Whitesides, G. M. J. Am. Chem. Soc. 1994, 116, 4298–4304. (h) Zerkowski, J. A.; Seto, C. T.; Whitesides, G. M. J. Am. Chem. Soc. 1992, 114, 5473–5475. (11) McMahon, J.; Peterson, M.; Zaworotko, M. J.; Shattock, T.; Hickey, M. B. WO Patent, WO 2006/007448 A2, 2006. (12) Kastelic, J.; Hodnik, I.; ket, P.; Plavec, J.; Lah, N.; Leban, I.; Pajk, M.; Planinek, O.; Kikelj, D. Cryst. Growth Des. 2010, 10, 4943–4953. (13) Kastelic, J.; Lah, N.; Kikelj, D.; Leban, I. Acta Crystallogr. C 2011, 67, o370–o372. (14) Product Monograph: Diflucan (Fluconazole); Pfizer Canada Inc.: Kirkland, Quebec, 2004. (15) Blagden, N.; Matas, M.; Gavan, P. T.; York, P. Adv. Drug Delivery Rev. 2007, 59, 617–630. (16) Stahl, H. P.; Wermuth, C. G. In Handbook of Pharmaceutical Salts - Properties, Selection and Use; Verlag Helvetica Chimica Acta: Zurich, 2002. (17) Childs, S. L.; Stahly, G. P.; Park, A. Mol. Pharmaceutics 2007, 4, 323–338. (18) McMahon, J.; Peterson, M.; Zaworotko, M. J.; Shattock, T.; Hickey, M. B. WO Patent, WO 2006/007448 A2, 2006. (19) (a) Wenger, M.; Bernstein, J. Mol. Pharmaceutics 2007, 4, 355–359. (b) Vishweshar, P.; McMohan, J. A.; Oliveria, M.; Peterson, M. L.; Zaworotko, M. J. J. Am. Chem. Soc. 2005, 127, 16802–16803. (c) Bond, A. D.; Boese, R.; Desiraju, G. R. Angew. Chem., Int. Ed. 2007, 46, 615–617. (d) Bond, A. D.; Boese, R.; Desiraju, G. R. Angew. Chem., Int. Ed. 2007, 46, 618–622. (20) Frisch, M. J. et al. Gaussian 03, revision B.05; Gaussian, Inc.: Pittsburg, PA, 2003. (21) APEX2, SADABS and SAINT; Bruker AXS Inc.: Madison, Wisconsin, USA, 2008. (22) Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.; Puschmann, H. J. Appl. Crystallogr. 2009, 42, 339–341. (23) Farrugia, L. J.; WinGx J. Appl. Crystallogr. 1999, 32, 837–838. (24) Sheldrick, G. M. Acta Crystallogr. A. 2008, 64, 112–122. (25) Macrae, C. F.; Bruno, I. J.; Chisholm, J. A.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Rodriguez-Monge, L.; Taylor, R.; van de Streek, J.; Wood, P. A. J. Appl. Crystallogr. 2008, 41, 466–470. (26) Nardelli, M. J. Appl. Crystallogr. 1995, 28, 569. (27) (a) McKinnon, J. J.; Jayatilaka, D.; Spackman, M. A. Chem Commun. 2007, 3814–3816. (b) Spackman, M. A.; McKinnon, J. J. CrystEngComm 2002, 4, 378–392. (28) (a) Chopra, D.; Guru Row, T. N. CrystEngComm 2008, 10, 54–67. (b) Chopra, D.; Guru Row, T. N. Cryst. Growth Des. 2008,

’ ASSOCIATED CONTENT

bS

Supporting Information. All the crystal structures are deposited with CCDC and the depository numbers are 816585 816588. The CIFs are also provided as Supporting Information along with tables which mention the cocrystallization experiments in detail and relevant PXRD DSC and TG data. Hirshfeld surface analysis data and fingerprint plots are provided. This information is available free of charge via the Internet at http://pubs.acs.org/.

’ AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Phone: 00911722240124. Fax: 00911722240266.

’ ACKNOWLEDGMENT We acknowledge Dr. K. Nagarajan for providing a sample of fluconazole monohydrate for this study. We thank Dr. Samrat Mukhopadhyay and Ms. Neha Jain for their help in recording the Raman spectra, Dr. Ramesh Ramachandran for useful discussion in analyzing the Raman spectra and Dr. Andrew Bond for useful discussion in analyzing PXRD data. MK thanks Department of Science and Technology (DST), India for research fellowship, SD thanks Indian Institute of Science Education and Research, Mohali (IISERM) for post-doctoral research fellowship and ARC thanks DST for the funding of the fast track project entitled “Co-crystallization of Active Pharmaceutical Ingredients Pathway for Enhanced Properties”. IISERM is acknowledged for providing single crystal and powder X-ray diffraction facility, research and other infrastructural facilities. ’ DEDICATION This publication is dedicated to Prof. K. Venkatesan on the occasion of his 80th birthday. ’ REFERENCES (1) Richardson, K. Pfizer Inc., U.S. Patent Application, US4404216, 1983. (2) (a) Richardson, K.; Cooper, K.; Marriott, M. S.; Tarbit, M. H.; Troke, P. F.; Whittle, P. J. Rev. Infect. Dis. 1990, 12, S267–271. (b) Richardson, K.; Cooper, K.; Marriott, M. S.; Tarbit, M. H.; Troke, P. F.; Whittle, P. J. Ann. N. Y. Acad. Sci. 1988, 544, 4–11. (3) Lo, J. B.; Mackay, G. G.; Puz, M. J. U.K. Patent Application, GB 2270521 A, 1994. 251



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8, 848–853. (c) Nayak, S. K.; Reddy, M. K.; Guru Row, T. N.; Chopra, D. Cryst. Growth Des. 2011, 11, 1578–1596. (29) McCrone, W. C. In Physics and Chemistry of the Organic Solid State; Fox, D.; Labes, M. M.; Weissberger, A., Eds.; Interscience Publishers, London, 1965, 2, 725767.

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New Polymorphs of Fluconazole: Results from Cocrystallization

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