Fluconazole Cocrystals with Dicarboxylic Acids - Crystal Growth


Oct 6, 2010 - Synopsis. Three novel cocrystals of fluconazole with maleic acid, fumaric acid, and glutaric acid have been identified. Primary intermol...
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DOI: 10.1021/cg1010117

Fluconazole Cocrystals with Dicarboxylic Acids )

)

#   Joze Kastelic,† Ziga Janez Plavec,# Nina Lah, Ivan Leban,*, Hodnik,‡ Primoz Sket, † ‡ Matjaz Pajk, Odon Planinsek, and Danijel Kikelj*,‡

2010, Vol. 10 4943–4953

 Krka, d.d., Novo mesto, Smarje ska cesta 6, SI-8501 Novo mesto, Slovenia, ‡University of Ljubljana, Faculty of Pharmacy, A sker ceva 7, SI-1000 Ljubljana, Slovenia, #Slovenian NMR Center, National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, Slovenia, and Faculty of Chemistry and Chemical Technology, University of Ljubljana, A sker ceva 5, SI-1000 Ljubljana, Slovenia )



Received August 2, 2010; Revised Manuscript Received September 13, 2010

ABSTRACT: Fluconazole cocrystals were prepared with the intention to modify physicochemical properties of the antifungal agent. The well-known COOH 3 3 3 Narom heterosynthon was considered the key element in the cocrystals design strategy. Cocrystals of fluconazole with maleic, fumaric, and glutaric acid were identified in solution evaporation experiments with pharmaceutically acceptable dicarboxylic acids and their crystal structures are presented. Solid-state NMR as an alternative technique for providing structural information of cocrystals offered additional insights into hydrogen bonding and other interas well as intramolecular interactions.

Introduction Most of active pharmaceutical ingredients (APIs) exist in the solid state and are commonly incorporated into solid dosage forms such as tablets and capsules which generally present the most convenient way for their application and storage.1-3 The molecular structure of an API determines its therapeutic properties and together with its solid form structure, that is, molecular arrangement within the solid, determines its unique physicochemical properties such as solubility, dissolution rate, hygroscopicity, physicochemical stability, mechanical properties, and others.1,4-7 If physicochemical properties of an API essential for formulation development and efficacy of a drug product are attempted to be influenced, this can be traditionally achieved on a molecular level with the formation of salts, hydrates/solvates, preparation of different polymorphic forms of all types of crystalline phases (neutral APIs, salts), and formation of amorphous forms.3,8 However, in recent years pharmaceutical cocrystals have emerged as an additional option with the potential to regulate important pharmaceutical properties such as processing characteristics, bioavailability, and stability,9,10 and also to provide highly relevant intellectual property implications.6,11,12 Numerous definitions of cocrystals have been proposed5,13-15 depending how broadly the term is defined, and a common definition still remains a matter of considerable discussion in the current literature.2,16-20 In the sense of a new variety of distinct solid forms, cocrystal is defined as a multicomponent single phase crystal composed of at least two components in a stoichiometric ratio. Components of cocrystals are solid under ambient conditions when in their pure form, and at least one of the components has to be in a neutral form.19 In the case in which an API in neutral or in ionized form is one of the components, the term pharmaceutical cocrystal is commonly used.8 Cocrystal former in pharmaceutical cocrystal must be pharmaceutically acceptable and nontoxic. It can comprise pharmaceutical excipients, food additives, or another API. 21,22

Fluconazole [2-(2,4-difluorophenyl)-1,3-bis (1H-1,2,4 triazole-1-yl)-propan-2-ol] (Figure 1) is a wide spectrum triazole antifungal agent, used in the treatment of localized candidiasis and systemic therapy of candidial infections, dermatophytic fungal infections, and cryptococcal meningitis. It is commonly used as accompanying therapy for immunodeficient patients, that is, patients with AIDS or cancer and patients taking immunodepressive agents.23 Three different polymorphic forms, a monohydrate and several solvates of fluconazole, are known,25-29 and single crystal structures of polymorph III, monohydrate and ethyl acetate solvate are available.25 Fluconazole is a very weak base with a pKa value of 1.76 for its conjugated acid, which limits its ability to form salts.30 It is generally accepted that for salt formation a pKa difference greater than two units between the acid and the base is needed,21,31,32 which means that only very strong acids would be considered appropriate for salt screening. Fluconazole is mainly administered orally in the form of tablets and capsules. As it is only slightly soluble in water, several strategies have been tried to enhance its dissolution rate in order to improve its local and/or systemic antifungal effectiveness including isolation of new polymorphs and solvates,24 granulation of fluconazole with an agent providing hydrophilic character of the granules,33 preparation of solid dispersions,34 and preparation of orally dispersible formulation.35 The literature reported only one structurally characterized fluconazole cocrystal: fluconazole maleate maleic acid hydrate.36 This inspired us to search for new fluconazole cocrystals with special attention given to the cocrystallization with pharmaceutically acceptable cocrystal formers as a viable means to improve its physicochemical properties. Experimental Section

*To whom correspondence should be addressed. E-mail: [email protected] fkkt.uni-lj.si (I.L.); [email protected] (D.K.).

Starting Materials. Fluconazole was obtained from Krka, Novo mesto, and identified as form III by powder X-ray diffraction (PXRD). Maleic acid, fumaric acid, glutaric acid, malic acid, and tartaric acid were obtained from Merck, and succinic acid was obtained from Fluka. All chemicals were used without further purification. Solvents (purity g99.9%) were obtained from Merck.

r 2010 American Chemical Society

Published on Web 10/06/2010

pubs.acs.org/crystal

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Solution-Based Cocrystal Screen of Fluconazole. Screening experiments were based on slow evaporation of mixed solutions in which fluconazole was combined with one of six dicarboxylic acids (fumaric acid, succinic acid, malic acid, tartaric acid, glutaric acid, and maleic acid) in different stoichiometric molar ratios. Generally, each cocrystal former was tested with several different solvents such as acetonitrile, acetone, ethanol, ethyl acetate, and tetrahydrofurane. The solutions were prepared by dissolving fluconazole and respective dicarboxylic acid in an appropriate solvent assisted by heating. The clear solutions were then cooled to ambient temperature and in some cases put in the refrigerator and allowed to evaporate slowly. The obtained solids were routinely characterized by melting point determination, powder X-ray diffraction, and IR spectroscopy. 1H NMR spectroscopy in DMSO-d6 was used to establish the molar ratio of fluconazole and cocrystal former. If the formation of cocrystals was confirmed, single crystal X-ray structure determination of the corresponding single crystals was attempted in an array of solutions based on slow evaporation experiments. (H2fluc)2þ(Hmal)2-(H2mal) Cocrystal 1:2:1 (1). A 1:3 mixture of fluconazole (fluc) (100.0 mg, 0.33 mmol) and maleic acid (H2mal) (113.3 mg, 0.99 mmol) was dissolved in 1.5 mL of ethyl acetate in a 20 mL vial by heating at 50 °C. The vial with clear solution was closed and put into the refrigerator until the crystals started to grow. Afterward, the content of the vial was allowed to evaporate to dryness at ambient temperature, and crystals were dried at ambient conditions for 96 h. Crystals suitable for single crystal X-ray diffraction were prepared similarly by dissolving fluconazole (200.0 mg, 0.66 mmol) and maleic acid (227.5 mg, 1.98 mmol) in 3 mL of ethyl acetate with heating at 50 °C. Closed vials were put in the refrigerator until the first crystals started to grow. The solvent was then allowed to evaporate very slowly at ambient conditions until crystals of suitable size and quality grew.

Figure 1. Structure of fluconazole (fluc).

Kastelic et al. (fluc)2(H2fum) Cocrystal 2:1 (2). A 2:1 mixture of fluconazole (fluc) (200.0 mg, 0.66 mmol) and fumaric acid (H2fum) (37.9 mg, 0.33 mmol) was dissolved in 1.8 mL of boiling ethanol. The clear solution was slowly cooled to ambient temperature, and solvent was then allowed to evaporate very slowly to dryness. Crystals were dried at ambient conditions for 96 h. Crystals suitable for single crystal X-ray diffraction were prepared by dissolving fluconazole (200.0 mg, 0.66 mmol) and fumaric acid (37.9 mg, 0.33 mmol) in 1 mL of boiling methanol. Seeds from screening experiment were added to clear solution, and the mixture was slowly cooled to ambient temperature. The solvent was then allowed to evaporate very slowly until the crystals of suitable size and quality grew. (fluc)(H2glut) Cocrystal 1:1 (3). A 1:1 mixture of fluconazole (fluc) (100.0 mg, 0.33 mmol) and glutaric acid (H2glut) (43.1 mg, 0.33 mmol) was added to 1 mL of acetonitrile and dissolved by heating at 50 °C. The clear solution was slowly cooled to ambient temperature, and solvent was then allowed to evaporate to form a transparent film from which crystals grew in 72 h and were subsequently dried at ambient conditions for 72 h. Crystals suitable for single crystal X-ray diffraction were prepared by dissolving fluconazole (100.0 mg, 0.33 mmol) and glutaric acid (43.1 mg, 0.33 mmol) in a mixture of acetonitrile (0.5 mL) and n-hexane (0.75 mL) by heating at 50 °C. Seeds from screening experiments were added to clear solution. The mixture was slowly cooled to ambient temperature and allowed to evaporate slowly until crystals of suitable size and quality grew. Melting Point Determination. Melting point of cocrystals was determined on a Leica hot-stage microscope and are uncorrected. Infrared (IR) Spectroscopy. IR spectra were acquired on PerkinElmer Spectrum BX FTIR spectrophotometer in KBr diffuse reflectance mode. The spectra were measured over the range of 4000 to 450 cm-1. Differential Scanning Calorimetry (DSC). DSC measurements were carried out on a Mettler Toledo Differential Scanning calorimeter DSC1 equipped with STARe Software v9.10. The heating rate was either 1 °C/min or 10 °C/min in the range from -10 to 160 °C under a dry nitrogen atmosphere (flow rate 40 mL/min). Powder X-ray Diffraction (PXRD). PXRD patterns were  recorded on a Philips XPert Pro MPD powder diffractometer, equipped with a Ni-filtered Cu KR radiation and a RTMS X’Celerator detector. The tube voltage and amperage were set at 45 kV and 40 mA. A step size of 0.033° (2θ) and a step time of 100 s over a scanning range of 3-31° in 2θ were applied. Solution 1H NMR. Solution 1H NMR spectra were recorded on a 300 MHz Bruker Avance DPX300 spectrometer. The samples were dissolved in DMSO-d6 and TMS was used as an internal standard. Solid-State NMR Spectroscopy (SSNMR). 1H magic angle spinning (MAS) NMR spectra were obtained on a Varian NMR System 600 MHz NMR spectrometer using a 3.2 mm NB Double Resonance HX MAS Solids probe at a spinning rate of 20 kHz. 13C cross polarization/magic angle spinning (CP/MAS) NMR spectra were

Table 1. Molecular Structures of Cocrystal Formers, Their pKa Values and Melting Point Data for Starting Materials, New Cocrystals and Published Fluconazole Maleate Maleic Acid Cocrystal36 (Melting Point of Fluconazole is 138-140°C)

a

Literature values of pKa and melting points from refs 44 and 45. b See ref 36.

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obtained on a Varian Unity Inova 300 MHz NMR spectrometer using a 5 mm Magic Angle VT CP/MAS probe at a spinning rate of 5 kHz. Single Crystal X-ray Diffraction (SC-XRD). Single crystal X-ray data were collected on a Nonius Kappa CCD diffractometer with graphite monochromated Mo KR radiation (λ = 0.71073 A˚) at 150 K. Data reduction and integration were performed by DENZO-SMN package.37 The structures were solved by direct methods implemented in SHELX-97 package and refined by a full-matrix least-squares method on F2 against all reflections using the same program.38 Hydrogen atoms were placed in geometrically calculated positions and refined using a riding model, except those of the protonated carboxylic groups and those of the protonated endocyclic N-atoms, which are found in a Fourier difference map and freely refined in all the reported structures. The H-atom of the fluconazole hydroxo group of the cocrystal 3 was refined freely, while those in the cocrystals 1 and 2 were placed in calculated positions and refined as riding on their parent atoms. Crystallographic data are listed in Table 2.

Results and Discussion In crystal packing of known structures of fluconazole polymorph III and ethylacetate solvate, the heterosynthon OH 3 3 3 N (arom.) is the key element of intermolecular interactions.25 Aromatic nitrogen is a pro-synthon which is quite frequently used in supramolecular synthesis of cocrystals.19 Usually it forms heterosynthon with carboxylic OH group.9,39-41 It has been also proven as a reliable synthon in cocrystallization Table 2. Crystallographic Data for Fluconazole Cocrystals cocrystal

1

2

3

formula formula weight crystal system space group T (K) a (A˚) b (A˚) c (A˚) R (°) β (°) γ (°) V (A˚3) Z Fcalc (g/cm3) μ (mm-1) R1 (all data) R1 (I > 2σ(I )) wR2 (all data) wR2 (I > 2σ(I )) goodness-of-fit

C25H24F2N6O13 654.50 triclinic P1 150(2) 5.49830(10) 13.8723(4) 18.4331(5) 98.0620(10) 91.748(2) 95.479(2) 1384.34(7) 2 1.570 0.137 0.0733 0.0569 0.1627 0.1516 1.126

C15H14F2N6O3 364.32 triclinic P1 150(2) 8.4151(3) 10.0035(4) 10.6165(3) 75.077(2) 86.219(3) 76.054(2) 838.10(5) 2 1.444 0.119 0.0662 0.0425 0.1073 0.0961 1.033

C18H20F2N6O5 438.40 triclinic P1 150(2) 5.6897(2) 10.6590(3) 17.0635(5) 72.909(2) 84.453(2) 80.863(2) 975.22(5) 2 1.493 0.124 0.0642 0.0400 0.0944 0.0846 1.011

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screening of the related triazole antifungal drug itraconazole with 1,4-dicarboxylic acids which presents a good starting point for cocrystallization experiments with fluconazole.9 Solid phases obtained from solution based cocrystal screening were first evaluated by melting point determination, IR, PXRD, DSC, and solution 1H NMR. The structures of cocrystal formers, their pKa values, and melting point comparisons between starting materials and cocrystals are presented in Table 1. Melting points of cocrystals 1 and 2 are lower than that of fluconazole and both cocrystal formers maleic and fumaric acid. The lowest melting point was determined for cocrystal 3 which is practically identical with the melting point of pure glutaric acid. Determined melting points are also correlate well with the results of DSC analysis (Figure S1, Supporting Information). Endothermic melting peaks in DSC curves showing thermal behavior of cocrystals are narrow and no signals at higher temperatures indicating the presence of pure components can be seen. In DSC curves of pure glutaric acid, a small endothermic peak is additionally present above 70 °C due to a known solid-solid transformation to a phase that melts at 96 °C.42,43 The PXRD pattern for fluconazole was identical to the one reported for polymorphic form III.24 PXRD confirmed that fluconazole formed new solid phases practically with all six dicarboxylic acids. For combinations with succinic, malic, and tartaric acid, peaks of starting materials were still present in diffractograms, while with maleic, fumaric, and glutaric acid completely new patterns were obtained indicating the generation of new solid forms. PXRD patterns for starting compounds and new forms are shown in Figure S2, Supporting Information. Comparison of simulated and measured powder diffraction patterns for cocrystal 1 indicates unexpected splitting of the reflection at ca. 7.5 deg in the pattern in Figure S2, Supporting Information. Also, there is an unexpected reflection at roughly the same position in the measured pattern for cocrystal 2, which could be a fluconazole monohydrate impurity. The formation of cocrystals with maleic, fumaric, and glutaric acid was also confirmed with IR spectroscopy where the spectrum of each cocrystal differed from the spectra of fluconazole and cocrystal former. Change of position, intensity, and shape of most of absorption bands in the spectra of new solid phases indicated that these were not just ordinary physical mixtures (Figures S3-S6, Supporting Information). The stoichiometric ratios of components in cocrystals were determined with the solution 1H NMR spectroscopy in

Table 3. Hydrogen Bond Parameters for Cocrystals 1-3a cocrystal 1

2 3

D-H 3 3 3 A O21A-H1A 3 3 3 O11A O11C- H1C 3 3 3 O22C O1-H1 3 3 3 O12Ca O21B-H1B 3 3 3 O21Cb O11B-H2C 3 3 3 O12Ac N14-H14 3 3 3 O21Cd N24-H24 3 3 3 O11Ac N24-H24 3 3 3 N21 O1-H1 3 3 3 O12Ca O1-H1 3 3 3 N14 O2F-H1F 3 3 3 N24e O22A-H2A 3 3 3 N24f O1-H1 3 3 3 N12g O11A- H1A 3 3 3 N14h

D-H (A˚) 0.97(3) 1.09(4) 0.82 0.95(5) 0.85(5) 0.93(3) 1.03(4) 1.03(4) 0.82 0.82 0.94(3) 1.00(3) 0.85(2) 0.98(3)

d(H 3 3 3 A) (A˚) 1.48(3) 1.34(4) 1.90 1.74(5) 1.81(5) 1.72(3) 1.63(4) 2.50(4) 2.51 1.99 1.77(3) 1.74(3) 2.18(2) 1.73(3)

d(D 3 3 3 A) (A˚) 2.455(3) 2.433(2) 2.665(2) 2.684(3) 2.652(3) 2.648(3) 2.658(3) 3.108(3) 2.843 2.7934(16) 2.7068(17) 2.7289(16) 2.9161(17) 2.7012(17)

Θ (D-H 3 3 3 A) (deg) 176(3) 178(4) 155.5 172(4) 176(5) 173(3) 175(3) 117(2) 105.9 164.7 175(2) 171(2) 144(2) 175(2)

a Symmetry codes: a: x þ 1, y, z. b: x - 1, y, z. c: -x þ 2, -y, -z þ 1. d: -x þ 2, -y, -z þ 1. e: -x þ 1, -y - 2, -z þ 4. f: -x þ 2, -y, -z þ 1. g: x - 1, y, z. h: -x þ 3, -y þ 1, -z þ 1.

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Figure 2. An ORTEP view of an asymmetric unit of cocrystal 1 with the atomic numbering scheme. Thermal ellipsoids are drawn at the 30% probability level.

DMSO-d6. The stoichiometric ratios for three new cocrystals 1-3 with maleic, fumaric, and glutaric acid were 1:3, 2:1, and 1:1, respectively (Figures S7-S10, Supporting Information). Crystal Structures. The crystal structures of the new cocrystals 1-3 were determined by single-crystal X-ray diffraction. Crystallographic data are summarized in Table 2, and hydrogen bond parameters are listed in Table 3. (H2fluc)2þ(Hmal)2-(H2mal) Cocrystal 1:2:1 (1). Cocrystal 1 crystallizes from ethyl acetate in a triclinic space group P1. Its asymmetric unit consists of fluconazole dication and three different crystallographically independent maleic acid species: two hydrogen maleate anions and a neutral maleic acid molecule. As such, it could be denoted as a maleic acid cocrystal of fluconazolium dimalete salt. For simplicity reasons, we use the term cocrystal 1 throughout the text. A view of an asymmetric unit is depicted in Figure 2. As expected, strong intramolecular hydrogen bonds of O-H 3 3 3 O type are formed within each of the hydrogen maleate anions. Additionally, an O-H 3 3 3 N hydrogen bond contact was observed within the H2fluc cation. The crystal packing is based on an eight-component centrosymmetric assembly depicted in Figure 3a. In such an arrangement, one of the Hmal- anions (C) interacts with two H2fluc cations through charge-assisted Nþ-H(triazole) 3 3 3 O-(carboxylate) and O-H(hydroxy) 3 3 3 O(carboxy) hydrogen bonds. The second Hmal- species (A) forms additional charge-assisted Nþ-H(triazole) 3 3 3 O-(carboxylate) hydrogen bonds. Neutral maleic acid molecule (B) forms O-H(carboxy) 3 3 3 O-(carboxylate) hydrogen bonds with the species C. So constructed eight-membered assemblies are further connected through hydrogen bonds between neutral maleic acid molecule (B) and Hmal- (A) anion of a neighboring unit, thus generating a staircase structural motif propagating along the a-axis (Figure 3b). Chains of staircases pack parallel to each other along the a-axis and are held together through weak C-H 3 3 3 O and C-H 3 3 3 F interactions (Figure 3c). According

Kastelic et al.

to the crystal structure, cocrystal 1 can be described as a maleic acid cocrystal of fluconazol dimaleate salt. (fluc)2(H2fum) Cocrystal 2:1 (2). Cocrystal 2 crystallizes from ethanol in triclinic space group P1. The asymmetric unit consists of one molecule of a neutral fluconazole molecule and one-half of a fumaric acid molecule. Fluconazole molecules form centrosymmetric dimers via O-H(hydroxy) 3 3 3 N(triazole) hydrogen bonds. A similar structural motif was observed also in a crystal of fluconazole polymorph III.25 Such dimers are connected through fumaric acid molecules located at the inversion center into infinite chains via hydrogen bonds of O-H 3 3 3 N(triazole) type (Figure 4a). Zig-zag chains stack along the a-axis by weak C-H 3 3 3 N, C-H 3 3 3 O, and C-H 3 3 3 F interactions forming zigzag sheets. Stacked sheets are held together by weak C-H 3 3 3 N interactions (Figure 4b). (fluc)(H2glut) Cocrystal 1:1 (3). Cocrystal 3 crystallizes in triclinic space group P1 with one neutral fluconazole molecule and one neutral glutaric acid molecule in the asymmetric unit. Fluconazole and glutaric acid form a zigzag (wave-like) chain by connecting carboxylic groups with nitrogens at position 4 of triazole rings through O-H(carboxy) 3 3 3 N(triazole) hydrogen bonds (Figure 5a). Chains stack along a-axis forming zigzag sheets by cross-linking fluconazole molecules via O-H(hydroxy) 3 3 3 N(triazole) hydrogen bonds. The sheets stack in an offset manner being held together by weak C-H 3 3 3 O and C-H 3 3 3 F interactions (Figure 5b). Fluconazole possesses two nitrogen atoms at positions 2 and 4 in each triazole ring that can act as hydrogen bond acceptors and a hydroxy group which can participate in hydrogen bonding as a proton acceptor or proton donor. Dicarboxylic acids have been used as cocrystal formers with carboxylic groups acting as strong hydrogen bond donors and/or weak acceptors. The carboxylic group forms heterosynthon with heterocyclic N-atom in all three structurally characterized cocrystals as expected. Only nitrogen at position 4 of the triazole ring participates in heterosynthon as it is less sterically hindered. Two heterosynthon types have been actually observed in cocrystals 1-3, namely, heterosynthon I and a charge-assisted heterosynthon II (Scheme 1). Fluconazole is a weak base with pKa 1.76 and according to higher pKa values of applied dicarboxylic acids salt formation has not been expected. Our expectation was confirmed in the case of cocrystals with fumaric and glutaric acid, while the compound with maleic acid crystallizes as salt with the additional neutral lattice maleic acid molecule. The proton location in the crystal structure of 1 indicates proton transfer between two maleic acid molecules and N-atom at position 4 of both triazole rings forming fluconazol dimaleate, while the neutral maleic acid molecule does not interact with fluconazole. The neutral or ionic nature of heterosynthons I and II can be also distinguished from structural characteristics of interacting functional groups, that is, from C-O bond lengths of carboxylic/carboxylate group and endocyclic C-N-C bond angle in the triazole ring. In neutral carboxylic group, C-O distances are longer relative to CdO distances, while in the carboxylate anion, depending on the extent of delocalization of negative charge between oxygen atoms, there can be practically no difference in distances between carbon and both oxygen atoms.46 The C-N-C angle in N-heterocycles is known to be sensitive to the protonation of nitrogen where cationic forms exhibit higher values than the corresponding neutral molecules.2,19,47-49

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Figure 3. Structural characteristics of cocrystal 1; (a) hydrogen bonding pattern of a discrete eight component assembly, (b) staircase structural motif along the a-axis composed of vertically linked succeeding layers of fluconazole: maleic acid 2:6 assemblies, (c) projection of packed chains of staircase motif in the bc plane.

In cocrystal 1, the C-O and CdO distances in maleic acid molecule A are 1.314(3) A˚ and 1.222(3) A˚ for carboxylic group, while for ionized carboxylate group the distances are 1.298(3) A˚ and 1.234(3) A˚ suggesting a localization of negative charge on the oxygen atom involved in the intramolecular hydrogen bond and the Nþ-H(triazole) 3 3 3 O-(carboxylate) bond. In maleic acid molecule B the C-O/CdO distances for carboxylic groups are 1.322(3) A˚/ 1.219(3) A˚ and 1.317(3) A˚/1.213(3) A˚. A clear distinction between the carboxylic group and carboxylate anion can be seen in maleic acid molecule C where C-O/CdO distances of 1.301(3) A˚/1.232(3) A˚ for the former and 1.258(3) A˚/ 1.268(3) A˚ for the latter are expected values. In cocrystals 2 and 3, values for C-O and CdO distances are 1.3154(19) A˚/1.2093(19) A˚ in fumaric acid molecule and 1.3255 (18) A˚/1.2058(19) A˚ and 1.3290(19) A˚/1.203(2) A˚ for carboxylic groups of glutaric acid molecule confirming that there is no proton transfer in the crystal structures (Table 4).

The C-N-C bond angles involving protonated nitrogens at position 4 of triazole rings in 1 are 106.6(2)° and 106.2(2)°. In 2 and 3 the values for C-N-C angles involving both unprotonated nitrogens at position 4 of triazole rings are lower and comparable [101.94(12)°, 102.52(13)° for 2 and 103.18(12)°, 102.67(13)° for 3]. It is interesting to note that C-N-N angles involving unprotonated nitrogen atoms at position 2 of triazole rings are similar with angle values spanning the range from 101.58(12)° to 103.45(19)°. Solid-State NMR Spectra. Proton transfer and hydrogen bonding in cocrystals 1-3 has been also evaluated with solidstate NMR. Solid-state NMR spectroscopy has proven to be a valuable technique for characterization of structure, conformation, and dynamics of molecular solids.50 It presents a complementary technique to the X-ray crystallography which is regarded as arguably the most powerful tool for structure determination.51-53 Solid-state NMR can be used for characterization of solid forms obtained from cocrystal screening experiments especially when single-crystal X-ray

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Figure 4. Structural characteristics of cocrystal 2; (a) fluconazole dimers connected through fumaric acid into infinite chains, propagated along the ab diagonal and (b) 3D network of cocrystal 2.

data are not available.54 As a more discriminating technique, it often provides information that can explain opposing results obtained with other analysis such as IR, Raman spectroscopy, and powder X-ray diffraction and can be helpful in verifying that a cocrystal has actually formed.53,54 It can be used as complementary information suggesting starting structure and/or structural restraints which simplify determination of crystal structure from PXRD data and not only to confirm that the resulting structure is reasonable.51,55 In some cases, it is possible to derive full crystal structure only from the NMR data.51 1 H MAS and 13C CP/MAS NMR experiments have been widely used to provide information about interactions and that local environment that are informative about the arrangement of molecules in solid form structure.53 Signals of protons participating in hydrogen bonding are of special interest as it is known that hydrogen bonding causes substantial high-frequency shifts of proton resonances. The shift of deshielded signal is dependent on the strength of the hydrogen bond which is reflected in the distance between the heavy atoms involved and the position of the hydrogen within that distance.51,55 The difference in 13C chemical shifts indicates the existence of different solid forms and can also give information about the number of molecules in the crystallographic asymmetric unit.55 Conversion from carboxylic to carboxylate form is manifested in the movement of respective 13C chemical shift to higher frequencies.56 The 1H MAS and 13C CP/MAS NMR spectra of cocrystals 1, 2, 3 and starting materials are shown in Figures 9-13. It can be clearly seen that the spectra of the cocrystals are distinctive from the spectra of starting materials confirming the formation of new solid forms.

The proposed assignment of solid state NMR spectra is based on available literature data for 1H and 13C chemical shifts of dicarboxylic acids, their ionized derivatives and fluconazole as well as on results of semiempirical calculations where the 1H chemical shift is correlated with hydrogen bond geometry. Two concepts which are based on neutron diffraction crystal structure analyses and have a given similar relative chemical shift positioning have been used for calculations. For the first one, the 1H chemical shift is linearly correlated with the proton-acceptor (H 3 3 3 A) distance,57 while for the second one the calculation is based on a more complicated correlation of the 1H chemical shift with both donor-proton (D-H) and proton-acceptor (H 3 3 3 A) distances derived from valence bond order model.58-60 As X-ray diffraction responds to electrons rather than nuclei, d(D-H) and d(H 3 3 3 A) values obtained from single crystal data are not considered appropriate for correlation calculation. In X-ray diffraction measurements on single crystals, the positions of heavy atoms participating in hydrogen bonds are well established, while the hydrogen is frequently poorly located. Therefore, theoretical D-H and H 3 3 3 A distances have been determined by D-H bond length calculations presented by Steiner, the concept of which is also based on the valence bond order model of hydrogen bonding.61 Those values are expected to be better than the ones derived from X-ray diffraction. Fluconazole. In 1H MAS spectrum of fluconazole (Figure 6a), no resolved downfield signal corresponding to O-H(hydroxy) 3 3 3 N(triazole) hydrogen bonded proton is observed, which is in agreement with the reported X-ray crystal structure of fluconazole form III.25 This is most probably due to a longer hydrogen bond with the donor-acceptor (O 3 3 3 N)

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Figure 5. Structural characteristics of cocrystal 3; (a) hydrogen bonding pattern and (b) 3D network of 3.

Scheme 1. Heterosynthons Formed in 1-3 Resulting from Carboxylic Acid 3 3 3 N (triazole) Hydrogen Bonding Interactions

Table 4. Carbon-Oxygen Bond Distances of the Carboxylic/Carboxylate Groups in Cocrystals 1-3 cocrystal 1

carboxylic acid -

Hmal (A) H2mal (B) Hmal- (C)

distance of 2.848 A˚. The respective signal could be hidden and overlapped with the broad signal corresponding to aromatic and aliphatic protons of fluconazole. Two sharp signals at smaller chemical shift values are ascribed to protons of water molecules present in the sample. In the spectrum of a dried sample, these two signals are not observed. Intensities of signals in 13C CP/MAS spectrum of fluconazole (Figure 6b) are weak, and some of them cannot be distinguished from the noise. Nevertheless, the resolved signals were assigned by comparison to chemical shifts of solution 13C NMR spectrum of fluconazole64 (see Table 5). Maleic Acid and Cocrystal 1. Two crystal forms are known for maleic acid and an essentially planar ring of maleic acid molecule formed with short intramolecular hydrogen bond is

2

H2fum

3

H2glut

d(C-O) (A˚)

d(CdO) (A˚)

1.298(3) 1.314(3) 1.322(3) 1.317(3) 1.301(3) 1.258(3) 1.3154(19) 1.3154(19) 1.3255(18) 1.3290(19)

1.234(3) 1.222(3) 1.219(3) 1.213(3) 1.232(3) 1.268(3) 1.2093(19) 1.2093(19) 1.2058(19) 1.203(2)

the basic unit in both forms. Each maleic acid molecule is connected with two equivalent intermolecular hydrogen bonds to two neighboring maleic acid molecules.62,63 The deshielded 1H resonances in spectrum of maleic acid (Figure 7a) observed at δ 13.2 and 16.0 ppm are therefore assigned to two protons of carboxylic groups involved in intermolecular and intramolecular hydrogen bonds, respectively. In 1H MAS spectrum of cocrystal 1 (Figure 7b), four deshielded signals for protons involved in hydrogen bonds at δ12.2, 12.9, 17.3, and 18.8 ppm are observed, which confirm formation of hydrogen bonds different from those present in

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pure maleic acid. The signal at δ18.8 ppm is assigned to protons involved in the strongest intramolecular hydrogen bonds in ionized molecules A and C of maleic acid as presented in crystal structure of 1 (see Figure 3). For comparison, a chemical shift of δ19.1 ppm has been observed for protons involved in intramolecular hydrogen bond in sodium hydrogen maleate.58 According to semiempirical calculations, the signal at δ17.3 corresponds to both Nþ-H(triazole) 3 3 3 O-(carboxylate) hydrogen bonds, while signals at δ12.9 and 12.2 ppm are assigned to carboxylic protons of maleic acid molecule B involved in intermolecular hydrogen bonding. Intermolecular hydrogen bonds between maleic

Figure 6. (a) 1H MAS NMR spectra and (b) spectra of fluconazole form III.

13

C CP/MAS NMR

Figure 7. 1H MAS NMR spectra of (a) maleic acid and (b) cocrystal with maleic acid (1). Table 5.

13

C atom M(C1) M(C2) M(C3) M(C4) Fu(C1, C4) Fu(C2, C3) G(C1, C5) G(C2, C4) G(C3) F(C1, C3) F(C2) F(C7, C12) F(C9, C14) F(C15) F(C16) F(C17) F(C18) F(C19) F(C20)

acid molecules in 1 are slightly longer than intermolecular bonds in crystalline maleic acid,63 so the corresponding chemical shifts have slightly lower δ values relative to the signal in samples of maleic acid (δ13.2 ppm). The O-H(hydroxy) 3 3 3 O(carboxy) hydrogen bond between hydroxylic proton of fluconazole and maleic acid molecule C is shorter (O 3 3 3 O distance of 2.665 A˚) than the O-H(hydroxy) 3 3 3 N(triazole) hydrogen bond in pure fluconazole. The corresponding signal could be observed as a shoulder on the downfield side of the broad signal between δ9 and 10 ppm. 13 C CP/MAS spectrum of maleic acid exhibits four different signals (Figure 8a) in agreement with the known crystal structure of maleic acid where olefinic and carboxylic C atoms are not equivalent. Chemical shifts are practically equivalent to the values reported by Ilczyszyn et al.63 The assignment according to reference data is presented in Table 5. The chemical shifts observed in 13C CP/MAS spectrum of cocrystal 1 relative to the values obtained for fluconazole and maleic acid confirm interactions between both components (Figure 8b). For carboxylic C atoms, four resolved signals at δ173.5, 171.2, 169.2, and 167.6 ppm are observed. The shape of peaks and respective intensity ratio of 2:2:1:1 (for totally six carboxylic C-atoms) suggests that three molecules of maleic acid participate in the asymmetric unit of cocrystal structure, which is in agreement with solved crystal structure of 1. With respect to the published data,63,65 the signals at

Figure 8. 13C CP/MAS NMR spectra of (a) maleic acid and (b) cocrystal with maleic acid (1).

C CP/MAS NMR Chemical Shifts of Fluconazole (F), Maleic Acid (M), Fumaric Acid (Fu), Glutaric Acid (G), Cocrystal 1, Cocrystal 2, and Cocrystal 3a fluconazole δ (ppm)b

maleic acid δ (ppm)c

fumaric acid δ (ppm)

glutaric acid δ (ppm)

172.8/(173) 133.3/(133) 140.1/(140) 169.3/ (169)

cocrystal 1 δ (ppm)

cocrystal 2 δ (ppm)

169.2, 173.5 132.2, 135.9 139.3 167.6, 171.2 172.5 136.4

168.4 134.9 181.5 33.8 18.7

55.6/(55.3) 74.4/(74.0) 151.3/(151.1) 146.6/(145.5) -d /(123.5) - /(130.1) - /(111.4) - /(159.5) - /(104.4) - /(162.3)

cocrystal 3 δ (ppm)

58.3 74.2 147.1 143.9 121.5 125.1 113.7 157.9 107.1 161.5

55.5 74.4 151.5, 150.5 146.9 124.8 129.7 159.1 161.8

175.5 30.4, 33.4 19.5 57.7 76.6 154.0 143.6, 146.2 122.1 127.7 113.5 158.6 105.8 161.6

a The numbering scheme of fluconazole and maleic acid is shown in Figure 9. b Solution 13C NMR values taken from ref 64. c 13C CP/MAS NMR values taken from ref 63. d - Intensities too low (not distinguished from noise).

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Figure 11. 13C CP/MAS NMR spectra of (a) fumaric acid and (b) cocrystal with fumaric acid (2). Low intensity signals in (a) are the spinning sidebands of two main signals. Figure 9. Atoms numbering scheme of (a) fluconazole, (b) maleic acid, (c) fumaric acid, and (d) glutaric acid.

Figure 12. 1H MAS NMR spectra of (a) glutaric acid and (b) cocrystal with glutaric acid (3). Figure 10. 1H MAS NMR spectra of (a) fumaric acid and (b) cocrystal with fumaric acid (2).

δ173.5 and 171.2 ppm are assigned to ionized carboxylic groups interacting with protonated triazole nitrogens and carboxylic groups involved in intramolecular hydrogen bonds of maleic acid molecules A and C, respectively. Ionization of the carboxylic group results in deshielding by þ0.7 and þ1.9 ppm relative to the values for crystalline maleic acid. Signals at δ169.2 and 167.6 ppm therefore most probably correspond to carboxylic C-atoms of nonionized molecule B which does not form intramolecular hydrogen bonds. According to known chemical shifts for ionized maleic acid,63 signals at δ139.3 and 135.9 ppm are ascribed to olefinic carbon atoms of ionized molecules A and C, while because of the absence of intramolecular hydrogen bonds in molecule B there is a common signal for both olefinic carbon atoms at δ132.2 ppm. Shielding of triazole C atoms due to protonation of nitrogen at position 4 shifts the signals to δ147.1 and 143.9 ppm. The signal at δ143.9 ppm is broad which indicates that triazole rings are in different environments resulting in slightly shifted signals for C atoms. Fumaric Acid and Cocrystal 2. The 1H MAS NMR spectrum of fumaric acid (Figure 10a) shows a deshielded signal at δ13.0 ppm. Two polymorphs (R- and β-form) are known for fumaric acid with similar layered crystal packing.66,67 Both contain molecular chains interlinked via hydrogen bonded carboxylic groups ; a homosynthon known for self-association of carboxylic acids through centrosymetric dimers forming a ring. Accordingly, the deshielded signal is assigned to protons of intermolecular hydrogen bonded carboxylic groups. In the 1H MAS NMR spectrum of cocrystal 2 (Figure 10b), a deshielded signal for protons involved in hydrogen bonding is observed at δ15.0 ppm. It can be concluded that in cocrystal 2 a new hydrogen bond has been formed. The signal is shifted downfield by 2.0 ppm relative to the signal for fumaric acid which indicates that the new hydrogen bond is stronger than the one in the fumaric acid. From the crystal structure, it is evident

that actually two different hydrogen bonds are present. The signal at δ15.0 ppm has been assigned to the strongest O-H (carboxylic) 3 3 3 N (triazole) hydrogen bond, while for a O-H(hydroxy) 3 3 3 N(triazole) hydrogen bond linking fluconazole dimers no deshielded signal is expected similar to fluconazole polymorph III. In 13C CP/MAS spectrum of fumaric acid, only two signals at δ136.4 and 172.5 ppm for olefinic carbons and carboxylic groups are observed (Figure 11a). In the 13C CP/MAS spectrum of cocrystal 2 signals of both fumaric acid and fluconazole are observed (Figure 11b). The signal at δ168.4 ppm corresponds to carboxylic C atoms involved in O-H (carboxy) 3 3 3 N (triazole) hydrogen bonding. The chemical shift of the carboxylic group signal indicates that COOH groups are not ionized, which is in agreement with the crystal structure of cocrystal 2. The signal for olefinic CH groups is found at δ134.9 ppm. Signals of triazole C atoms are shifted only slightly with respect to pure fluconazole (Table 5), confirming that hydrogen bonded nitrogen at position 4 is not protonated. The overlapped signals at δ150.5 and 151.5 ppm which are assigned to C7 and C12 atoms indicate that triazole rings are located in different environments. Glutaric Acid and Cocrystal 3. Two polymorphic forms (R and β) are known for glutaric acid.68 Both forms have similar identity periods and geometries of the unit cells. Molecular chains are interlinked via hydrogen bonding carboxylic groups forming “carboxylic ring”. Therefore, the only deshielded signal in 1H MAS NMR spectrum of glutaric acid (Figure 12a) observed at δ12.9 ppm is assigned to the intermolecular hydrogen bonded carboxylic group. In the 1H MAS NMR spectrum of cocrystal 3 (Figure 12b), signals of two overlapped peaks at δ13.2 and 14.1 ppm are shifted downfield with respect to the signal observed for protons involved in hydrogen bonds in pure glutaric acid indicating formation of different hydrogen bonds. The signals were assigned to unequal O-H (carboxy) 3 3 3 N(triazole) hydrogen bonds influenced by different local environment interactions. From the crystal structure of 3, it can be seen that the carboxylic

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the generality of our observations to other fluconazole dicarboxylic acid cocrystals as well as the optimization of largescale synthesis are in progress. Supporting Information Available: DSC curves, XRPD patterns, IR spectra, and solution 1H NMR spectra of fluconazole, cocrystal formers, and cocrystals 1, 2, and 3. X-ray crystallographic information files (CIF) are available for cocrystals 1, 2, and 3. This material is available free of charge via the Internet at http://pubs.acs.org.

Figure 13. 13C CP/MAS NMR spectra of (a) glutaric acid and (b) cocrystal with glutaric acid (3). Low intensity signals present in (b) are the spinning sidebands of main signals.

group and triazole ring forming one of hydrogen bonds additionally interact by weak C-H(phenyl) 3 3 3 O(carboxy) and C-H(triazole) 3 3 3 F(phenyl) hydrogen bonds with the difluorophenyl group participating in stacking of assembled sheets (see Figure 5b). The nitrogen at position 2 of the same triazole ring is also hydrogen bonded with the hydroxylic group of the neighboring fluconazole molecule. This is a weak hydrogen bond with a donor-acceptor (O 3 3 3 N) distance of 2.916 A˚, and similarly as for the fluconazole sample it can be expected that the chemical shift of the hydroxylic proton overlaps with the broad signal between δ6 and 10 ppm. The 13C CP/MAS spectrum of glutaric acid shows three signals at δ18.7, 33.8, and 181.5 ppm that are assigned to the central CH2 group, two lateral CH2 groups, and two COOH groups, respectively (Figure 13a). In the 13C CP/MAS spectrum of cocrystal 3, the shift of the carboxylic C-atoms signal to δ175.5 ppm with respect to pure glutaric acid suggests changes in hydrogen bonding (Figure 13b). The broader signal indicates that two carboxylic C-atoms are in different environments, which is in agreement with overlapped signals for O-H(carboxy) 3 3 3 N(triazole) hydrogen bonds in the 1H MAS spectrum. Signals at δ30.4 and 33.4 ppm for C-atoms of two lateral CH2 groups next to carboxylic groups additionally confirm the unequivalence of both ends in glutaric acid, and the signal of the central CH2 group has been shifted to δ19.5 ppm (Table 5). For triazole C-atoms, three signals are observed at δ154.0, 146.2, and 143.6 ppm signifying that triazole rings are located in different environments. As previously discussed for the 1H spectrum of 3, one of the triazole rings besides hydrogen bonding with the carboxylic OH group also interacts with the difluorophenyl group and with the hydroxylic group of the neighboring fluconazole molecule. Conclusion Three novel cocrystals of fluconazole with maleic acid, fumaric acid, and glutaric acid have been prepared with the solution evaporation method and fully characterized by single crystal X-ray diffraction, 1H MAS and 13C CP/MAS NMR spectroscopy. It is evident from the solved crystal structures that primary intermolecular interactions are based on hydrogen bonding between the carboxylic OH group and heterocyclic nitrogen atoms of fluconazole. Interestingly, proton transfer from the carboxylic group to aromatic nitrogen took place in the case of cocrystal with maleic acid. This happened even though the pKa difference between the acid and the base is much lower from the generally accepted pKa difference of two units required for salt formation. The findings of this study will help us in advanced fluconazole cocrystals screening and synthesis. Studies to discern

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