Co-Crystals and Co-Crystal Hydrates of the ... - ACS Publications

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Co-Crystals and Co-Crystal Hydrates of the Antibiotic Nitrofurantoin: Structural Studies and Physicochemical Properties Published as part of the Crystal Growth & Design virtual special issue In Honor of Prof. G. R. Desiraju Venu R. Vangala,*,† Pui Shan Chow,† and Reginald B. H. Tan*,†,‡ †

Crystallisation and Particle Science, Institute of Chemical and Engineering Sciences, A*STAR (Agency for Science, Technology and Research), 1, Pesek Road, Jurong Island, Singapore, 627833 ‡ Department of Chemical and Biomolecular Engineering, National University of Singapore, 4, Engineering Drive 4, Singapore 117576 S Supporting Information *

ABSTRACT: The current contribution aims to prepare a family of nitrofurantoin (NF) co-crystals and to investigate the ability of these co-crystals in enhancing the photostability and clinically relevant physicochemical properties of NF. Accordingly, supramolecular synthesis of the antibiotic drug NF with the coformers 3-aminobenzoic acid (3ABA), 4-aminobenzoic acid (4ABA), urea, 4-hydroxybenzamide (4HBAM), phenazine (PHEN), melamine (MELA), 4,4′-bipyridine (BIPY) and 1,2-bis(4-pyridyl ethane) (BIPE) have produced five co-crystals and three co-crystal hydrates. Solid-state physical characterizations have been conducted by powder X-ray diffraction (PXRD), single crystal X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot-stage microscopy (HSM) and spectroscopy (Raman and 1H NMR). Crystal structures have been analyzed based on homo- and heterosynthons. Six out of eight multicomponent crystals are primarily stabilized by heterosynthons, whereas the remaining two co-crystals (NF-4ABA and NF-UREA) contain homosynthons. Notably, thermal analysis of co-crystal hydrates showed high thermal stability (∼166 °C, NF-MELA-H2O) or upon dehydration provided new anhydrous co-crystals, NF-BIPY and NF-BIPE in a 2:1 molar ratio. Physicochemical properties such as aqueous solubility, intrinsic dissolution rate and photostability have been investigated for NF-3ABA, NF-4ABA, NF-UREA and NF-4HBAM. Co-crystals display enhanced physicochemical properties as compared to that of NF: NF-4HBAM > NF-3ABA > NF-4ABA > NF-UREA > NF (β-form). The results suggest that co-crystals can be a viable alternative for improving the biopharmaceutical properties of API.

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INTRODUCTION Crystal engineering plays a decisive role in the systematic design and synthesis of functional materials by means of exerting a control on the intermolecular interactions.1 In recent years, there has been an enormous growth in interest devoted to the area of pharmaceutical co-crystallizations2 alongside polymorphs,3 hydrates,4 salts,5 and amorphous materials6 by the pharmaceutical industry and academia. Co-crystallization of active pharmaceutical ingredients (APIs) and pharmaceutically acceptable co-formers, generally recognized as safe (GRAS) materials,7 offers a new approach for improving the physicochemical properties of APIs such as melting point,8 aqueous solubility, dissolution rate,9 physicochemical stability,10 tablet compression− manufacturability11 and bioavaialability.12 These novel materials have a great potential in the expansion of intellectual property of the APIs.13 In this context, a recent perspective has highlighted the definition and classification of co-crystals.14 Nitrofurantoin (NF) is a widely used antibacterial drug for the oral treatment of genitourinary tract infections.15 It is a Biopharmaceutics Classification System (BCS) Class II drug, which has both low solubility and permeability. The drug dose © 2012 American Chemical Society

is 50 or 100 mg in tablet form and as an oral liquid 25 mg/ 5 mL is administered. It has been reported that the dissolution rate and bioavailability of NF in commercial tablets decreased upon storage at different temperature and relative humidity conditions.16 Otsuka and co-workers suggested that the physicochemical stability of NF could be one of the critical factors for controlling the bioavailability of commercial preparations.16 On the other hand, NF is known to be a photosensitive drug.17 Exposure to sun or fluorescent light has been reported to cause discoloration in NF crystals and its solutions.18 These characteristics can significantly impact the therapeutic activity of the drug.19 Several NF polymorphs and pseudopolymorphs have been reported before.20,21 NF exists in both anhydrous (α- and β-) and hydrate (Forms I and II) polymorphic forms. We prepared a first co-crystal22 based on NF with 4-hydroxybenzoic acid (4HBA), and our findings demonstrated that co-crystal can significantly improve the storage stability and offered protection Received: July 2, 2012 Revised: October 12, 2012 Published: October 18, 2012 5925

dx.doi.org/10.1021/cg300887p | Cryst. Growth Des. 2012, 12, 5925−5938

Crystal Growth & Design

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Scheme 1. Chemical Structures of NF and Co-Formers

liquid-assisted grinding (NG, LAG) investigations26 were carried out with stoichiometric amount of NF (1 mmol) and co-former (1 mmol) in a 1:1 molar ratio. For all LAG experiments, acetonitrile was used as the solvent because of its optimal solubility with API and co-formers in this study. 50 μL of acetonitrile was added to 200 mg of reactants mixture prior to LAG (η = 0.25 μL mg−1).26b The external temperature of the grinding jar at the end of grinding did not exceed 30 °C. The resulting powder samples were analyzed by powder X-ray diffraction. Solution Crystallizations. NF (β-form, 1 mmol) and a stoichiometric amount of co-formers (1 mmol) were dissolved in 30 mL of acetonitrile at 70 °C. Similarly, NF-UREA was prepared from methanol (70 mL) and NF-MELA-H2O was obtained from an equimolar mixture of acetonitrile and water (40 mL). NF and co-former solutions were allowed to evaporate slowly at ambient conditions for two days to produce the multicomponent crystals. Powder X-ray Diffraction (PXRD). The powder diffraction data were collected in Bragg−Brentano geometry with a Bruker D8 Advance (Bruker AXS GmbH, Germany) X-ray powder diffractometer equipped with Cu−Kα radiation (λ = 1.54056 Å) source, a Nickel-filter, 0.3° divergence slit and a linear position sensitive detector (Vantec-1). The diffractometer was operated at 35 kV and 40 mA. The sample was loaded onto a glass circular sample holder that has 1 mm thickness and 1.5 cm diameter. The data were collected over an angle range of 2θ 3 to 50° with a scanning speed of 2° 2θ per minute. Single Crystal X-ray Diffraction. Single crystals of all co-crystals except for NF-4HBAM was chosen under a Leica microscope and placed on a fiber needle which was then mounted on the goniometer of the X-ray diffractometer. The crystal was purged with a cooled nitrogen gas stream at 110 K throughout the data collection. X-ray reflections were collected on a Rigaku Saturn CCD area detector with graphite monochromated Mo-Kα radiation (λ = 0.71073 Å).

to UV-light as compared to that of NF. Recently, Alhalaweh and co-workers performed a screening for co-crystals of NF using 47 co-formers, out of which seven were identified as co-crystals.23 In another study, hydration stability and dissolution rate were reported for NF and 4-aminobenzoic acid co-crystal.24 The current contribution aims to prepare an array of NF co-crystals and to investigate the ability of these co-crystals in enhancing the photostability, and clinically relevant physicochemical properties such as aqueous solubility and dissolution of NF. Accordingly, NF was set out to co-crystallize with various co-formers based on the molecular attributes present in both NF and co-formers (see Scheme 1). NF is a planar molecule that has imide, nitro and activated C−H functionalities. The co-formers such as 3/4-aminobenzoic acid (3ABA, 4ABA), urea (UREA), 4-hydroxybenzamide (4HBAM), phenazine (PHEN), melamine (MELA), 4,4′-bipyridine (BIPY), 1,2-bis(4-pyridyl)ethane (BIPE) consist of acid, amine, amide, pyridyl and aryl sticky groups. For the multicomponent crystals discussed in this study, plausible supramolecular homo- and heterosynthons25 are illustrated in Scheme 2.

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EXPERIMENTAL SECTION

Materials. Nitrofurantoin (β-form) was obtained from SigmaAldrich, and all the co-formers were purchased from Alfa-Aeser and used as received. The solvents were of analytical or chromatographic grade. Grinding. It was performed on a Retsch Mixer Mill model MM301 with 10 mL stainless steel grinding jars and one 7 mm stainless steel grinding ball at a rate of 20 Hz for 30 min. Both neat and 5926



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Scheme 2. Some Plausible/Observed Homosynthons and Heterosynthons Between The Molecular Functionalities in The Co-Crystals

Hot-stage Microscopy (HSM). Thermomicroscopic investigations29 were performed with an optical polarizing microscope (Olympus, BX51, Olympus Optical GmbH, Vienna) equipped with a Linkam hot-stage THMS 600 connected to a TMS 94 temperature controller and a LNP 94/2 liquid nitrogen pump (Linkam Scientific Instruments Ltd., Tadworth, Surrey, UK). The microscopic images were recorded with a CCD camera attached to the microscope at 12 s time interval using Soft Imaging System’s Analysis image capture software. Samples (NF-MELA-H2O, NF-BIPY-H2O and NF-BIPEH2O) were heated over the temperature range of 25−300 °C at a constant heating rate of 10 °C min−1. The hot-stage was calibrated using USP melting point standards. High Performance Liquid Chromatography (HPLC). The NF content was analyzed by an HPLC (Agilent 1100 series) equipped with an Agilent Extend-C18 column (3.5 μm, 4.6 mm × 150 mm). Separations were conducted using the mobile phase of a mixture of pH 7.2 phosphate buffer and acetonitrile (88:12) at a gradient elution of 1.6 mL/min. An injected volume of 5 μL was used. Detection wavelength in the UV−visible was set at 375 nm. A linear calibration curve was constructed at a concentration range of approximately 5−100 μg/mL and with R2 of 0.99. All measurements were made in triplicates. Solubility and Intrinsic Dissolution Rate (IDR). The solubility studies for powder samples of NF (anhydrate and hydrate forms), coformers 3ABA, 4ABA, 4HBAM and UREA and its co-crystals were performed in aqueous media at 37 °C. Excess amounts (∼200 mg) of the samples were suspended in 7 mL of water in a 10 mL vial and the slurries were stirred at 600 rpm using a magnetic stirrer. After 20 h, the suspensions were withdrawn with a 1 mL syringe and passed through a nylon filter (0.2 μm). The filtered aliquots were sufficiently diluted and the content of NF was assayed using HPLC (Agilent 1100 Series) for NF and its co-crystals. The co-formers, 3ABA, 4ABA, UREA and 4HBAM, contents were determined using UV spectroscopy set at the wavelengths of 312, 286, 194, and 253 nm, respectively. Intrinsic dissolution experiments were performed using a USP certified Woods apparatus (Electrolab, Mumbai, India) adapted to

Data were collected and processed using CrystalClear (Rigaku) software. A single crystal of NF-4HBAM was mounted on a glass pip and intensity data were collected on a Bruker’s KAPPA APEX II CCD Duo system with graphite-monochromatic Mo-Kα radiation (λ = 0.71073 Å) at 100 K and the data reduction was performed using Bruker SAINT software. All crystal structures were solved by direct methods and SHELX-TL was used for structure solution and leastsquares refinement.27 The data of NF-4HBAM were refined using Cell_Now for a treatment of twinning. The non-hydrogen atoms were refined anisotropically. All hydrogen atoms were fixed at idealized positions except for the N−H and O−H hydrogens, which were located from the difference Fourier map and allowed to ride on their parent atoms in the refinement cycles. All N−H, O−H and C−H distances are neutron normalized to 1.009, 0.983, and 1.083 Å, respectively. X-Seed was used to prepare the packing diagrams. Data collection and refinement details are given in Table 1, and relevant hydrogen bonding interactions and their geometries are listed in Supporting Information. Cambridge Structural Database (CSD). A CSD28 search was conducted using ConQuest 1.14 (CSD version 5.33, Feb 2012 update) on heterosynthons (IV, VI, VII, VIII, IX and XI) involving imide/ dimide with various functionalities of co-formers used in a study. For all the searches, only the structures with 3D coordinates determined and “no errors”, “no polymeric”, “no ions”, “no powder” and “only organics” were considered. A 3D search on various synthons was performed using the acceptable bond distance and angle for each of the noncovalent interaction (N−H···O, O−H···O: 1.6−2.5 Å, 120−180°; N−H···N, C−H···O: 1.6−2.8 Å, 120−180°). A search fragment details are given in Supporting Information. Thermal Analysis. Simultaneous differential scanning calorimetry and thermogravimetric analysis (DSC-TGA) were performed with SDT 2960, TA Instruments. Crystals taken from the mother liquor were blotted dry on a filter paper and manually ground to obtain fine powder. Approximately, 5 mg of the sample was added to a crucible. The samples were heated over the temperature range of 25 to 300 °C at a heating rate of 10 °C/min. The samples were purged with a stream of flowing nitrogen throughout the experiment at 200 mL/min. 5927


5928

a

Packing fraction.

melting point (°C)

formula weight crystal system space group T [K] a [Å] b [Å] c [Å] α [°] β [°] γ [°] Z V [Å3] Dcalc [g cm−3] μ [mm−1] reflections used unique reflections observed reflections parameters R1 [I > 2σ(I)] wR2 [all] GOF Ck* [%]a crystal shape

empirical formula

NF-4ABA

(C8H6N4O5)·(C7H7NO2) 375.30 triclinic P1̅ 110(2) 9.1485(18) 6.7539(14) 9.4656(19) 7.4546(15) 9.903(2) 16.032(3) 107.39(3) 92.64(3) 98.66(3) 91.81(3) 97.17(3) 102.47(3) 2 2 795.8(3) 786.6(3) 1.566 1.585 0.127 0.129 11173 8995 3773 2748 3294 2460 260 264 0.0549 0.0524 0.1268 0.1319 1.149 1.145 72.7 73.8 orange red block orange needle 204.8 235.2

NF-3ABA

229.2

(C8H6N4O5)·(CH4N2O) 298.23 monoclinic P21/c 110(2) 6.6779(13) 13.648(3) 14.003(4) 90 110.95(3) 90 4 1191.9(5) 1.662 0.142 7309 2080 2033 190 0.0403 0.0958 1.114 75 yellow needle

NF-UREA

223.9

(C8H6N4O5)·(C7H7NO2)2 512.44 monoclinic P21/c 100(2) 6.810(2) 15.644(5) 21.120(7) 90 93.260(7) 90 4 2246.4(12) 1.515 0.120 31599 3668 2624 341 0.1147 0.2796 1.146 71.7 yellow needle

NF-4HBAM

NF-PHEN

234.2

(C8H6N4O5)·(C6H4N)2 418.37 triclinic P1̅ 110(2) 8.7234(17) 9.969(2) 11.547(2) 65.43(3) 86.27(3) 84.23(3) 2 903.3(3) 1.530 0.114 10009 3010 2595 300 0.0891 0.1943 1.218 73.1 brown block

Table 1. Crystallographic Data for Nitrofurantoin Co-Crystals and Co-Crystal Hydrates NF-MELA-H2O

166.1

(C8H6N4O5)·(C3H6N6)·(H2O) 382.32 triclinic P1̅ 110(2) 6.8748(14) 10.541(2) 11.088(2) 75.64(3) 82.27(3) 84.85(3) 2 770.0(3) 1.649 0.137 9105 2856 2740 280 0.0358 0.0946 1.098 74.5 yellow block

NF-BIPY-H2O

192.8

(C8H6N4O5)·(C5H4N)·(H2O) 334.28 monoclinic C2/c 110(2) 31.804(6) 6.7822(14) 13.672(3) 90 99.86(3) 90 8 2905.5(10) 1.528 0.124 16577 2556 2510 229 0.0672 0.1544 1.241 72.3 yellow plate

NF-BIPE-H2O

190.8

(C8H6N4O5)2·(C6H6N)2·(H2O)2 696.60 triclinic P1̅ 110(2) 6.4093(13) 13.597(3) 19.138(4) 106.54(3) 93.68(3) 100.76(3) 2 1558.3(5) 1.485 0.119 17186 5002 4193 491 0.0783 0.1764 1.203 70.8 yellow plate

Crystal Growth & Design Article



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Figure 1. Solid-state packing of NF-3ABA (1:1) viewed down the b-axis. Notice the acid-imide heterosynthon, synthon IV, between NF and 3ABA molecules. Varian VK7010 dissolution testing system with a VK750D heater/ circulator. For each experiment, 900 mL of pH 7.2 phosphate buffers were preheated to 37 °C and stirred at 100 rpm. Approximately, 100 mg of NF or equivalent amount of co-crystal was compressed to a 0.5 cm2 disk using a hydraulic press with a pressure of 2.5 ton/inch2 for 3 min. These samples were immersed in the dissolution media, and at a regular time interval 1.2 mL of the samples were withdrawn manually. The collected samples were filtered through 0.2 μm nylon filter and assayed for NF concentration using HPLC. The sample integrity after solubility, compression, and dissolution were characterized by PXRD. Photostability. It was carried out for NF+coformer physical mixtures and co-crystals of NF-3ABA, NF-4ABA, NF-UREA and NF4HBAM using Intelli-Ray shuttered UV flood light. The wavelength of the artificial UV light was in the range of 315 and 400 nm. Prior to UV irradiation, powder samples of physical mixtures and co-crystals were sieved and only sieved fractions of less than 300 μm were used in the experiments. UV exposure time points studied were 48 and 168 h for physical mixtures and for co-crystals 1, 3, 6, 12, 18, 24, 48, 72, and 168 h. NF content at each time point was analyzed by HPLC (Agilent 1100 Series). The UV irradiated powder samples were dissolved in acetonitrile and the content of NF was determined for each time point in triplicate.

reactions for the other combinations provided powder patterns that were different from the physical forms of the starting materials. The grinding experiments indicated that NF form multicomponent crystals with all the co-formers tested except for 2ABA. The multicomponent crystals obtained from grinding experiments were taken further for solution crystallization. While NF-3ABA (brick red blocks), NF-4ABA (orange needles), NF-UREA (yellow needles) and NF-PHEN (brown blocks) provided 1:1 stoichiometric co-crystals, NF-4HBAM (yellow needles) provided 1:2 co-crystal under the 1:1 stoichiometric crystallization conditions. The unintended co-crystal hydrates30,31 resulted with NF-MELA-H2O (1:1:1, yellow blocks), NF-BIPYH2O (1:0.5:1, yellow blocks) and NF-BIPE-H2O (1:0.5:1, yellow blocks) when NF and corresponding co-former were crystallized from acetonitrile. The PXRD patterns of these novel co-crystals and crystal morphologies are provided in the SI. Crystal Structure Analysis. Single crystal X-ray diffraction analyses were performed for eight multicomponent crystals. Crystallographic data are provided in Table 1. Hydrogen bonding geometries and crystallographic asymmetric units with ORTEP diagrams for these multicomponent crystals are provided in the SI. NF-3ABA (1:1) crystallizes in the triclinic, P1̅ space group with one molecule each of NF and 3ABA in the asymmetric unit. NF and 3ABA molecules adopt planar conformation. The imide of NF and acid of 3ABA form an expected imide−acid heterosynthon IV (Scheme 2, Figure 1) with O−H···O and N−H···O interactions (1.72 Å, 173°; 1.85 Å, 157°). It was noted that a strong and directional centrosymmetric C−H···O dimer (2.30 Å, 151°), homosynthon V, is formed between the activated C−H and nitro group of furyl ring in NF. Next, the primary NH2 of 3ABA is involved in bifurcated N−H···O (2.15 Å, 165°; 2.40 Å, 126°) or bifurcated N−H···O and N−H···N interactions (2.31 Å, 149°; 2.41 Å, 137°) with the available O/N acceptors of NF. The solid-state packing is further supported by C−H···O interactions to complete a sheet structure. The crystal structures of NF-4ABA and NF-UREA have been reported previously by Nangia and co-workers.24 To facilitate comparison with the novel co-crystals reported in this paper, a structural analysis of these co-crystals is also presented briefly. The crystal packing of NF-4ABA (1:1) (Figure 2) is shown to be stabilized by the acid dimer (1.61 Å, 175°) and imide dimer

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RESULTS AND DISCUSSION Grinding has emerged as an excellent experimental approach to rapidly and efficiently screen the formation of multicomponent crystals.26 Screening of NF (β-form) with simple regioisomeric monoaminobenzoic acids, namely, 2-, 3-, 4-aminobenzoic acids (2/3/4ABA), urea, 4-hydroxybenzamide (4HBAM), phenazine (PHEN), melamine (MELA), 4,4′-bipyridine (BIPY) and 1,2bis(4-pyridyl)ethane (BIPE) was conducted by solid-state neat and liquid-assisted grinding methods (NG, LAG). During grinding, the molecular recognition is expected to take place between imide of NF and co-former functionalities such as acid, amide and pyridyl groups to afford multicomponent crystals. The grinding experiments were performed using equimolar ratios to acquire preliminary information with minimum screening efforts. It was not meant as a comprehensive screen for all possible NF cocrystals stoichiometries. The resulting powder materials were analyzed by PXRD (Supporting Information, SI). Both NG and LAG powder patterns of NF with 2ABA matched with the starting materials, suggesting no co-crystal was formed. NF with 3ABA in NG has provided either unreacted starting materials or NFH2O (Form II), but a powder pattern different from that of the starting materials was obtained from LAG. Both NG and LAG 5929



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Figure 2. Solid-state packing of NF-4ABA (1:1) viewed down the b-axis. Notice the imide−imide and acid−acid homosynthons (III and I) within NF and 4ABA molecules, respectively.

Figure 3. (a) Solid-state packing of NF-UREA (1:1) viewed down the a-axis. Notice the amide dimer homosynthon II between the urea molecules, and N−H···O heterosynthon between imide-NH and carbonyl of urea. (b) A C−H···O dimer, homosynthon V, between nitro furyl ring connects the linear tape packing.

consists of NF and two symmetrically dependent 4HBAM molecules. The crystal packing was further supported by C−H···O interactions to complete a sheet structure. NF-PHEN (1:(0.5)2) crystallizes in the triclinic, P1̅ space group. A 1:(0.5)2 co-crystal, which can also be referred to as 1:1 stoichiometry, consists of one molecule of NF and two half molecules of PHEN in the asymmetric unit. NF molecule adopts a molecular conformation distinctive to those found in all co-crystals discussed in this study (SI), but a similar molecular conformation was observed previously with a pseudopolymorph, NF-dimethylsulfoxide (1:0.5) and a co-crystal, NF-2,6-diacetamidopyridine (1:1).21 The crystal structure of NF-PHEN shows an expected three point synthon, heterosynthon VIII (1.99 Å, 173°; 2.24 Å, 170°; 2.31 Å, 176°), between diimides of NF on either side of phenazine (half-1) molecule (Figure 5). Symmetrically independent phenazine (half-2) molecule participated in directional C−H···O hydrogen bonds (2.55 Å, 155°). It was also shown to have recurring nitro furyl hydrogen bonds, synthon V (2.45 Å, 154°). The overall crystal packing was stabilized by π−π stacking interactions. NF-MELA-H2O (1:1:1) crystallizes in the triclinic, P1̅ space group with one molecule each of NF, MELA and H2O (Figure 6). A notable synthon for the melamine and diimide molecular adducts are a three point motif, heterosynthon IX.33 The crystal structure of NF-MELA-H2O persists with the three point synthon IX between diimide of NF and pyridyl N (N−H···N, 1.77 Å, 176°)/adjacent NH groups of MELA

(1.83 Å, 166°) (homosynthons I and III) instead of heterosynthon IV observed in NF-3ABA. The acid dimer and imide dimers are in turn connected by aminophenyl−nitro interactions to form the sheet structure. The solid-state structure of NF-UREA (1:1) consists of amide dimer, homosynthon II (1.95 Å, 179°), between the urea molecules (Figure 3) and N−H···O (1.75 Å, 160°) hydrogen bonds between imide-NH of NF and carbonyl of urea. There are no urea tape or urea−nitro interactions, which are typical to urea and/or nitro containing molecules.32 Instead, amide NH2 participated in bifurcated N−H···O (2.23 Å, 149°; 2.51 Å, 120.5°) or bifurcated N−H···O and N−H···N (2.18 Å, 146°; 2.47 Å, 139°) hydrogen bonds with the O/N acceptors of NF. Herein the supramolecular (bifurcated) interactions of amide NH2 with NF is similar to that of the hydrogen bonds between primary NH2 and NF in the crystal structure of NF-3ABA. There was also assistance from a reliable nitrofuryl synthon V in the linear tape packing. A 1:2 co-crystal of NF-4HBAM was obtained from a 1:1 stoichiometric mixture of NF and 4HBAM from acetonitrile. It crystallizes in the monoclinic, space group P21/c with one molecule of NF and two molecules of 4HBAM in the asymmetric unit. The crystal structure is primarily stabilized by two synthons where amide-amine is mediated by CO (synthon VI, 1.86 Å, 158°; 2.00 Å, 137°; 2.13 Å, 164°) and amide-imide via phenolic OH, (synthon VII, 1.84 Å, 164°; 1.56 Å, 179°; 2.00 Å; 137°) (Figure 4). Synthon VI is formed between NF and two symmetrically independent 4HBAM molecules whereas synthon VII 5930



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Figure 4. Solid-state packing of NF-4HBAM (1:2) viewed down the a-axis. Two molecules of 4HBAM in the asymmetric unit were color coded with majenta and cyan. Notice the highlighted synthons formation between amide-amine and amide-imide are mediated by either CO or phenolic OH.

(N−H···O, 2.04 Å, 176°; 2.31 Å, 158°) (Figure 6). Water molecule strongly bonds with azine N of NF and pyridyl N of MELA molecules to form O−H···N interactions (2.02 Å, 161°; 1.85 Å, 165°). MELA molecules themselves form the centrosymmetric amine−pyridyl synthons (synthon X). Crystal packing was further supported by a frequently observed synthon in this group of compounds, furyl nitro dimer heteromeric interactions, synthon V (2.27 Å, 151°) to complete a sheet structure. Solid-state extended network shows the arrangement of sheets and interaction of water molecules within the sheet. Water molecules between the sheets are not interacting with each other (Figure 6b). NF-BIPY-H2O (1:0.5:1) crystallizes in the monoclinic, C2/c space group. The crystal structure was primarily stabilized by imide N−H and pyridyl N interaction assisted by C−H···O,

Figure 6. (a) Solid-state packing of NF-MELA-H2O viewed down the c-axis. Notice a strong three point synthon between NF and melamine. Water strongly bonds to azine N of NF and pyridyl N of MELA. (b) Lateral view of the sheets that incorporated water molecules.

heterosynthon XI (1.80 Å, 170°; 2.58 Å, 136°; Figure 7). The incorporated water molecule in the lattice bonds to the available O/N acceptors of NF. The same motif was observed in the crystal structure of a monohydrate polymorph of NF, NF-H2O (Form II).20 It appears that water incorporated in the lattice due to the availability of several O/N acceptors.30 The solid-state extended network consists of recurring nitro-furyl heteromeric interaction, synthon V, that completes a corrugated sheet structure (Figure 7b). Adjacent water molecules lie in the channels parallel to b-axis but they are not hydrogen bonded to each other.

Figure 5. Solid-state packing of NF-PHEN. Notice the robust three point synthon between NF and phenazine molecules. Symmetrically independent phenazine molecule involved in π−π stacking with nitrofuryl ring of NF. 5931



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Figure 7. (a) Solid-state packing of NF-BIPY-H2O viewed down the b-axis. Notice the heterosynthon between NF and BIPY molecules. (b) Corrugated sheet structure of NF-BIPE-H2O viewed down the c-axis. Water interacts with all the available acceptors in NF molecules.

Figure 8. (a) Solid-state packing of NF-BIPE-H2O viewed down the b-axis. Notice the water mediating hydrogen bonding interactions between NF and BIPE molecules. (b) View along the a-axis illustrates packing of water molecules in the tapes, C−H···O bonds are omitted between BIPE and NF molecules for clarity.

is close to our recently reported co-crystal, NF-4HBA.22 The arrangements of NF molecules in the lattice are similar in both NF-4HBA and NF-BIPE-H2O. Herein BIPE and water together are supramolecularly equivalent to 4HBA acid dimer in NF4HBA. Solid-state extended network along the a-axis shows the arrangement of tape structure and the interaction of water molecules within the tapes (Figure 8b). Adjacent water molecules in the 3D network are not hydrogen bonded to each other. CSD Analysis. A CSD28 search on heterosynthons IV, VI, VII, VIII, IX, and XI were performed to comprehensively understand the interactions between imide/diimide of NF with

A 2:(0.5) 2 :2 or 1:0.5:1 co-crystal of NF-BIPE-H 2O crystallizes in the triclinic, P1̅ space group. Although BIPE is an ethane homologue of BIPY, the interaction of the lattice water and crystal packing of NF-BIPE-H2O is different from that in NF-BIPY-H2O. In the solid-state structure, NF and BIPE molecules are held together by water molecules (Figure 8). Imide NH of NF bonds to O atom of water (N−H···O, 1.70 Å, 172°; 1.76 Å, 161°) that the water molecule in turn connects with pyridyl-N of BIPE (O−H···N, 1.87 Å, 168°; 1.84 Å, 163°) and adjacent NFs imide carbonyl (O−H···O, 1.84 Å, 171°; 1.87 Å, 171°). A detailed analysis reveals that the crystal structure 5932



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the various functionalities of co-formers and explore their statistical significance (SI). For analyses of synthons IV and XI, all five membered cyclic imides with any substitution on nonimide part of a molecule were retrieved from the CSD (SI). There were a total of 1290 hits available, of which 72 hits include both acid (x-COOH; X = any) and five membered imide containing molecules. Among these 72 hits, synthon IV has been observed in 23 hits (31.9%). Among a total of 1290 hits, 46 hits contain both pyridyl scaffold and cyclic imide molecules. In these 46 hits, synthon XI has been observed in three hits (6.5%). Without C−H···O in synthon XI, there were reasonable hits (20 hits, 43.5%). Hence, synthons IV and XI are expected to form when imide/acid or imide/pyridine functionalities are present in the single or multicomponent crystals. In order to understand the prevalence of two less common synthons (VI and VII) observed in the crystal structure of NF-4HBAM, all neutral primary amide (R-CONH2; R = C, H) hits were archived from the CSD (SI). There were a total of 1619 hits available, of which 29 hits (1.79%) display synthon VI and the synthon with amide−amide via OH (nonphenolic) were found in four crystal structures. Herein, amide-imide mediated by phenolic OH (synthon VII) was found to be the first example. For synthons VIII and IX, cyclic dimides with any ring length and substitution containing molecules were retrieved from CSD. There were a total of 1818 hits available, of which one hit was found to have both pyridyl diarene and diimide containing molecules and in that synthon VIII was observed. Among a total of 1818 hits, 83 hits contains both pyridyl diamine scaffold with any substitution and diimide molecules. Of these 83 hits, synthon IX was observed in 72 hits (86.7%). This information reveals that a three point motif, synthon VIII, is not an anomalous interaction and synthon IX is a preferred motif when diimide and pyridyl diamine functionalities are available in single or multicomponent crystals. Thermal Analysis. DSC and TGA. Thermal behavior of multicomponent crystals was assessed by the simultaneous DSC and TGA. There was no suggestion from TGA of included solvent for NF-3ABA (1:1), NF-4ABA (1;1), NF-UREA (1:1), NF-4HBAM (1:2) and NF-PHEN (1:1) (SI). DSC curves for these phases showed one major endotherm for each confirming the respective melting events (Table 2). It was immediately followed by degradation.

Table 3. Thermal Data (DSC and TGA) for the Co-Crystal Hydrates co-crystal hydrate NF-MELA-H2O NF-BIPY-H2O NF-BIPE-H2O

calcd % wt obsvd % wt Tonset for dehyd ΔH for dehyd loss loss (°C) (J g−1) 4.71 5.38 5.17

4.65 5.32 5.10

166.1 155.7 86.9

113 39 119.8

5.1%, respectively (Table 3). These can be attributed to the 1 mol of water for each of the composition. DSC curves were in agreement with the observed weight loss in the TGA traces with the appearance of corresponding endotherms at 155.7 and 86.9 °C. It was followed by melting of dehydrated samples at 192.8 and 190.8 °C respectively. It is to be mentioned that a direct correlation of chemical structure to crystalline lattice energy to melting point is a challenging task because of several contributing factors such as molecular arrangement in the lattice, noncovalent interactions and conformational flexibility for a molecule. It becomes more complex with the multicomponents crystals. Herein melting points of all the multicomponent crystals were in between the API and the corresponding co-former are in general agreement with co-crystals reported in the literature (SI, Table S2).2g,8a Further, melting point of co-crystals appears to alter with the co-former, meaning higher melting co-former should be selected if higher melting co-crystal is desired. HSM.29 The thermal events observed in the DSC/TGA experiments on co-crystal hydrates, NF-MELA-H2O, NF-BIPY-H2O and NF-BIPE-H2O, were visualized using HSM. The photomicrographs in Figures 9−11 show the snapshot images of the crystals at various temperatures during the experiments. Co-crystal hydrates were heated from RT to 300 °C. The HSM results were comparable with the DSC and TGA analyses except

Table 2. Thermal Data (DSC and TGAa) for the Co-Crystal

a

co-crystal

Tonset for melting (°C)

ΔH for melting (J g−1)

NF-3ABA NF-4ABA NF-UREA NF-4HBAM NF-PHEN

204.8 235.2 229.2 223.9 234.2

27.6 198.3 199.6 130.8 104.1

Figure 9. Photomicrographs of NF-MELA-H2O extracted from the HSM experiment.

TGA showed no weight loss until melting of the co-crystals.

A thermal analyses of the three co-crystal hydrates revealed the following results (Table 3, SI). The observed weight loss in the TGA of NF-MELA-H2O (1:1:1) is 4.65%, which is in accord with the weight loss of one mole of water for each mole of respective components of the crystal (Table 3). The DSC curve complemented well with the TGA that dehydration occurred with the onset temperature of 166.1 °C (SI). According to DSC/TGA traces, dehydration was followed by degradation/sublimation. Similarly, TGA traces of the NF-BIPY-H2O (1:(0.5):1) and NF-BIPE (2:(0.5)2:2) showed the weight loss of 5.32% and

Figure 10. Photomicrographs of NF-BIPY-H2O extracted from the HSM experiment. 5933



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Figure 11. Photomicrographs of NF-BIPE-H2O extracted from the HSM experiment.

that the thermal events were observed slightly slower in HSM by 2−5 °C. In HSM of NF-MELA-H2O, there was no change in the crystal morphology over the temperature range of 30−165 °C (Figure 9). Lattice water plays a significant role in stabilizing the solid-state structure. In the crystal structure, water was strongly hydrogen bonded to NF(azine N) and MELA(pyridyl N). From Figure 9, dehydration can be seen to occur from 168 °C, which was followed by the degradation/ sublimation of NF and MELA molecules. So, crystal structure collapses upon water loss. There was no visible change in the crystal morphology of NF-BIPY-H2O over the temperature range of 30−109 °C. From Figure 10, dehydration was seen to occur from 110 °C, which is in agreement with the DSC/TGA results (a detail of thermal profile given in SI, Figure S10). Dehydration was followed by a melting event at 194 °C. Next, NF (β-form) crystals were obtained from the melt at 210 °C (Figure S11, SI), which subsequently melted at ∼270 °C and this is consistent with DSC/TGA profiles. In the case of NF-BIPE-H2O, dehydration took place at 89 °C and melting occurred at 192 °C and is consistent with DSC/TGA profiles (Figure 11). The post melting events were similar to NF-BIPY-H2O. NF (β-form) crystals were obtained from the melt at 210 °C (SI, Figure S11), which subsequently melted at ∼271 °C and this is also consistent with DSC/TGA profiles. Dehydration Experiments. In general, removal of hydrate/ solvate from crystal lattice results in structural rearrangement with concomitant loss of crystallinity.34 Hence, outcome of the dehydration depends on the slight differences in the crystal structures. The crystalline hydrates were dehydrated at 120 °C for NF-MELA-H2O and 90 °C for NF-BIPY-H2O and NF-BIPEH2O in a vacuum oven (∼10 mbar pressure) for two days. The resulting dehydrated samples were analyzed by PXRD, DSC/ TGA and 1H NMR. Dehydrated phase of NF-MELA-H2O was analyzed to be NF (β-form), MELA and traces of NF-MELAH2O. It shows that water was strongly hydrogen bonded to NF and MELA molecules via N−H···N bonds and the lattice collapsed upon removal of water (SI). Interestingly, dehydrated materials obtained from NF-BIPYH2O and NF-BIPE-H2O were found to be the new phases as per PXRD (Figures 12 and 13). Thermal (DSC/TGA) and 1H NMR data revealed that the two novel phases were anhydrous co-crystals involving NF and BIPY or BIPE in 2:1 stoichiometry (SI). The crystal packing of NF-BIPY-H2O indicates that upon removal of water from its lattice channels, the novel anhydrous

Figure 12. Comparison of the PXRD patterns of NF, BIPY, a simulate pattern generated from a single crystal X-ray structure of NF-BIPYH2O and a product obtained from the dehydration experiment at 90 °C in a vacuum (∼10 mbar pressure) for 2 days.

Figure 13. Comparison of the PXRD patterns of NF, BIPE, a simulated pattern generated from a single crystal X-ray structure of NF-BIPE-H2O and a product obtained from the dehydration experiment at 90 °C in a vacuum (∼10 mbar pressure) for 2 days.

co-crystal, NF-BIPY (2:1), may retain synthon XI and rearrange the solid-state network. In the case of NF-BIPEH2O, dehydration led to a significant structural rearrangement, as water(O−H) involved in strong hydrogen bonding with (NF)imide CO (N−H···O and O−H···O) and (BIPE)pyridyl-N (O−H···N), and synthon XI may have formed to afford an anhydrate phase, NF-BIPE (2:1). The results suggest that co-crystal hydrates coud be an alternative route to prepare novel co-crystals that offer further avenues for expanding the new solid forms involving APIs. Physicochemical Properties of NF Co-Crystals. Physicochemical properties such as aqueous solubility, intrinsic dissolution rate and photostability of NF-3ABA, NF-4ABA, NF-UREA and NF-4HBAM were determined and compared with that of NF (β-form). Physicochemical properties of co-crystal hydrates and NF-PHEN were not evaluated because attempts to obtain quantity sufficient for performing physicochemical tests were not successful through batch crystallizations. Aqueous Solubility and Intrinsic Dissolution Rate (IDR). Solubility of NF (β-form), NF-H2O (Form II), coformers and NF co-crystals were measured in DI water at 5934



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Table 4. Equilibrium Solubility and IDR of NF and Its Co-Crystals API/cocrystal NF (β-form) NF-3ABA NF-4ABA NF-UREA NF-4HBAM

co-former solubility (mg mL−1) 9.5 7.7 1510 13

± ± ± ±

0.2 0.3 10 0.3

API or cocrystal solubilitya (mg L−1) 135 255 242 142 295

± ± ± ± ±

2 4 4 3 6

IDRb (μg cm−2 min−1) 35.8 59.6 53.3 41.4 91.3

a Solubility of NF-H2O (Form II) is 128 ± 2. bIDR, of API or co-crystal, measured with the exposure of surface area for 40 min.

37 °C. The equilibrium solubility values are provided in Table 4. The higher solubility of NF (β-form) than that of NF-H2O (Form II) is in agreement with the literature.20 The equilibrium solubility values of NF co-crystals are higher than that of NF(β-form) and NF-H2O (Form II). The co-formers solubility values are in the following order: UREA > 4HBAM > 3ABA > 4ABA. Interestingly, solubility trend of co-formers were followed in the co-crystals except for NF-UREA: NF-4HBAM > NF-3ABA > NF-4ABA > NF-UREA. All the other co-crystals remained after the solubility experiments did not show any phase transformations. The exception with NF-UREA can be explained by its conversion to NF-H2O (Form II) during the solubility experiment and is consistent with literature.24 Solubility difference between NF (∼135 mg L−1) and urea (∼151 × 104 mg L−1) is very high. Structurally, NF-UREA has strong hydrogen bonding interactions within the urea molecules compared to that of NF and urea (Figure 3). Therefore, NF-UREA has more propensities toward dissociation when exposed to aqueous media. As one anticipates, among regioisomers 3ABA and 4ABA, meta-isomer displayed higher solubility as compared to para-isomer.35 A similar tendency was retained in their co-crystals. The higher aqueous solubility trend of 4HBAM as compared to the solubilities of 3ABA and 4ABA was also preserved in their respective co-crystals. These results indicate that co-formers have a significant contribution in the solubility behavior of co-crystals. In addition, the interactions between co-former and API could impact the outcome.

Figure 14. Intrinsic dissolution profiles of NF (β-form) and NF cocrystals in pH 7.2 buffer. Dissolution profiles up to 150 min were provided in the Supporting Information.

As per the USP Pharmacopoeia guideline for NF, the intrinsic dissolution rates (IDRs) of NF (β-form), NF-3ABA, NF-4ABA, NF-UREA and NF-4HBAM were measured in pH 7.2 phosphate buffer at 37 °C. The IDR values are provided in Table 4 and Figure 14. It was calculated from 0 to 40 min of the dissolution curve or up to a linear regression of 0.99. The IDR values in pH 7.2 buffer are in the following order: NF-4HBAM > NF-3ABA > NF-4ABA > NF-UREA > NF (β-form). It indicates that all the co-crystals dissolve faster than commercial anhydrous NF (β-form). As per PXRD, the samples remained after the dissolution experiments for 150 min did not show any phase transformations except for NF-UREA. Crystal structure analyses further revealed that co-crystals formed with the heterosynthons,2a synthons VI and VII in NF-4HBAM and synthon IV in NF-3ABA, appear to be the preferred hydrogen bonding interactions to improve aqueous solubility and dissolution rate compared to that of co-crystals that are assisted by homosynthons (synthons I and III in NF-4ABA, synthon II in NF-UREA). Photostability. NF is known to be a photosensitive drug.17−19 It shows rapid photoisomerization about the C−N double bond

Scheme 3. Photodegradation Scheme of NFa

a

Note NF cleavage at the azomethine chain. 5935



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(Scheme 3).17b NF is cleaved at the azomethine chain to form 5-nitro-2-furaldehyde and 1-aminohydantoin upon UV irradiation. Our preliminary research findings showed that co-crystallization has a potential to circumvent the chemical degradation of API.22 In order to evaluate the generality of co-crystals to improve the photostability of API, co-crystals NF-3ABA, NF-4ABA, NF-UREA and NF-4HBAM were tested against pure NF (β-form) and physical mixtures of NF and co-former (NF+3ABA, NF+4ABA, NF+UREA and NF+4HBAM). NF co-crystals were distributed in watch glass aliquots and analyzed at various intervals during exposure with a 315− 400 nm UV lamp (1, 3, 12, 18, 24, 48, and 168 h).36 Physical mixtures were exposed to a UV light for 48 h and 168 h. Time dependent change in the NF content under UV irradiation was monitored. It was observed that degradation in pure NF (β-form, 27.7%)22 and in physical mixtures were similar (26 −30%) after 168h of UV irradiation (Figure 15). It reveals

screened. The resulting products were characterized by PXRD, single crystal X-ray diffraction, DSC, TGA, and HSM. Evaporative crystallization efforts resulted in five co-crystals and three co-crystal hydrates. We identified structure determining homo- and heterosynthons in a family of co-crystals involving NF. It was noted that NF-4ABA, NF-UREA were primarily stabilized by homosynthons, NF-BIPE-H2O consists of water mediated heterosynthons and in all other co-crystals heterosynthons were predominantly observed. Thermal studies indicated that melting points of all multicomponent crystals were in between those of API and co-former. It reveals that NF-MELA-H2O was thermally stable up to ∼166 °C and dehydration of NF-BIPY-H2O and NF-BIPE-H2O resulted in the identification of two new anhydrous co-crystals (NF-BIPY and NF-BIPE). Thus, co-crystal hydrates could be an alternative route to prepare novel co-crystals and offer further avenues for expanding the novel solid forms involving APIs. Aqueous solubility and intrinsic dissolution rates (IDRs) of co-crystals were superior to that of NF (β-form). The order of aqueous solubility and IDR inlcudes NF-4HBAM > NF-3ABA > NF-4ABA > NF-UREA > NF (β-form). Finally, we evaluated a generality of NF co-crystals to circumvent the photodegration of NF. Our findings show that co-crystals display superior photostability to that of NF. Overall, co-crystals display improved physicochemical properties as compared to that of NF. The results suggest that co-crystals can be a viable alternative for enhancing physicochemical and photostability of co-crystal over API.

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ASSOCIATED CONTENT

S Supporting Information *

X-ray crystallographic information files (CIF); crystal morphologies, ORTEP diagrams, PXRD patterns of the samples obtained in grinding experiments, hydrogen bond geometries, CSD search fragment details, dehydration experiments, IDR profiles up to 150 min, crystallographic information files (.cif) for cocrystals. CCDC reference numbers 860441−860448. This information is available free of charge via the Internet at http://pubs.acs.org/.

Figure 15. UV irradiation of co-crystal and physical mixture samples involving NF up to a week and the photodegradation curves with the error bars show the enhanced photostability of co-crystals. For a comparison, data for NF (β-form) are shown.20

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that physical mixtures did not offer any protection against photodegradation. Notably, all co-crystals degraded to a minor extent ( NF-3ABA > NF-4ABA > NFUREA. These results show that co-crystals generally display significantly superior photostability over NF. Improved photostability of co-crystals as compared to NF is attributed to restricted photoisomerization and prevention of direct availability of incident photons to CN of NF. For example, urea as a co-inclusion compound with 13-cis retinoic acid (cis-RA) was found to delay the photodegradation of the cis-RA when compared to pure cis-RA.37 Herein co-crystallization10d offers a modulated solid state packing for the API. The potential factors which could determine the degree of photoprotection includes (i) hydrogen bonding between NF and co-former, (ii) arrangement of co-crystal components within the crystal lattice, and (iii) sensitivity of co-former towards UV irradiation. The exact mechanism of the photostability improvement requires more detailed study and is the subject of our further research.

AUTHOR INFORMATION

Corresponding Author

*(V.R.V) E-mail: [email protected]. Tel: (65) 6796 3862. Fax: (65) 6316 6183. (R.B.H.T) E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by Science and Engineering Research Council of A*STAR (Agency for Science, Technology and Research), Singapore. V.R.V. thanks Prof. Gautam R. Desiraju for introducing to the motivating field of Crystal Engineering. We thank Tang Hui Shan, Grace Lau and Chia Sze Chen for their technical assistance and Dr. C. Malla Reddy and G. Rama Krishna, IISER-Kolkata, India, for their help with a single crystal X-ray diffraction data of NF-4HBAM.

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REFERENCES

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CONCLUSIONS In conclusion, the co-crystallization of an antibiotic drug, nitrofurantoin (NF), with eight co-formers have been successfully 5936



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