A Comparative Study of the Ionic Cocrystals NaX - ACS Publications

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A comparative study of the ionic cocrystals NaX (#-D-glucose)2 (X=Cl, Br, I) Kevin Linberg, Naveed Zafar Ali, Martin Etter, Adam A. L. Michalchuk, Klaus Rademann, and Franziska Emmerling Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b01929 • Publication Date (Web): 10 Jul 2019 Downloaded from pubs.acs.org on July 18, 2019

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Crystal Growth & Design

A comparative study of the ionic cocrystals NaX (α-D-glucose)2 (X=Cl, Br, I) Kevin Linberg 1,2, Naveed Zafar Ali 1, Martin Etter 3, Adam A.L. Michalchuk 1, Klaus Rademann 2,1 and Franziska Emmerling 1,2* Federal Institute for Materials Research and Testing (BAM), Richard-Willstaetter-Str. 11, 12489 Berlin, Germany 2 Department of Chemistry, Humboldt-Universität zu Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany 3Deutsches-Elektronen-Synchrotron (DESY), 22607Hamburg, Germany 1

KEYWORDS in situ; cocrystal; mechanochemistry; glucose;

Abstract The mechanochemical formation of the ionic cocrystals of glucose (Glc) and sodium salts Glc2NaCl*H2O (1) and Glc2NaX (X = Br (2), I (3)) is presented. Products are formed by comilling Glc with three sodium salts (NaCl, NaBr, NaI). The ionic cocrystals were obtained under both neat grinding and liquid-assisted grinding conditions with later found to accelerate the reaction kinetics. The crystal structures of the ionic cocrystals (2) and (3) were solved from powder X-ray diffraction data. The structure solution contrasts with the structure of Glc2NaCl*H2O (1) where the electron density at three halide crystallographic sites is modelled as of being the intermediate between water molecule and a chloride ion. The reaction pathways of the three ionic cocrystals were investigated in real time using our tandem approach comprising a combination of in situ synchrotron powder X-ray diffraction and Raman spectroscopy. The results indicate the rapid formation of each cocrystal directly from their respective starting materials without any intermediate moiety formation. The products were further characterized by DTA-TG and elemental analysis.

Introduction Cocrystals are monophasic crystalline materials that consist of at least two different molecules.1 These structures are stabilized by non-covalent interactions such as hydrogen bonds and π-π stacking, with hydrogen bonds being the dominant stabilizing interaction.

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During a reaction, non-covalent interactions are broken in the starting materials and are subsequently rebuilt to form the product. Multi-component crystals are becoming of increasing interest to the pharmaceutical industry, owing largely to their potential for modifying the physico-chemical properties of drugs.2 One such issue, associated with the development of new drugs, is the often low aqueous solubility and insufficient bioavailability of pharmaceutical molecules.3 While co crystals and salts have been demonstrated to mitigate some of these issues, the properties of ionic cocrystals (ICCs) are particularly promising in this direction.4 A definition of ICCs is still missing. Typically, three different types of ICCs are described.5 The first type is made of a neutral molecule, which builds hydrogen bonds to a salt formed by its anion or cation. For example, the cocrystal of benzoic acid and sodium benzoate.6 The second type consists of an organic molecule and an inorganic salt, like the cocrystal system barbituric acid and KBr.7 The third type is composed of two neutral molecules and a salt. As such, ICCs permit to combine the properties of a non-ionized organic molecule with those of inorganic salts.8 ICC structures typically arise from the interaction of an organic functional group with the anionic component of the salt, often through hydrogen bonds. In recent years, mechanochemistry has proved to be an excellent technique for the preparation of multi-component crystals. Mechanochemical syntheses are fast, high yielding and comply with many of the principles of green chemistry. This stems largely from the fact that mechanochemical methods require little (liquid-assisted grinding, LAG) or no solvent (neat grinding, NG).9 The solvent does not dissolve the components, but rather acts as a reaction catalyst, presumably by interaction with the particle surfaces. The mechanochemical formation of cocrystal has been studied intensively indicating an entanglement of different mechanisms. Rastogi and


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Singh have shown that cocrystals can be formed by molecular transport of symmetric and planar molecules across the surface.10 Alternatively, Chadwick et al. demonstrated that cocrystal formation can occur from an eutectic,11 while Jayasanker et al. have found evidence that cocrystals can form via an intermediate amorphous phase.12

An ICC of glucose and NaCl in 2:1 stoichiometry was reported by Calloud in 1825.13 The glucose-NaCl-H2O system was found soon after by Gill,14 with the phase diagram being corrected by Matsuura in 1927.15 The anhydrate16 and monohydrate17 both crystallize in the trigonal space group P31. The asymmetric unit of (D-glc)2NaCl contains six glucose molecules and three NaCl units. Each Na+ cation is surrounded by six oxygen atoms, from four glucose molecules. This results in formation of a distorted octahedral geometry around the Na+-centre. These octahedra are linked by hydrogen bonds (O-H…Cl and O-H…O), forming a three-dimensional framework. The only difference between the anhydrate and monohydrate crystal structures are the additional hydrogen bonds that form between H2O molecules and the Cl- anions. In 1863, Stenhouse described the ICC of glucose and NaBr.18 This was followed closely by the report of gluc-NaI ICC in 1893 by Traube.19 The hydrates (D-glc)2NaBr*H2O and (Dglc)2NaI*H2O was described by Rendle and Glazier in 1992.20 While authors were able to index diffraction patterns of both compounds in the trigonal space group P31, their structures could not be solved. Instead, they were assumed to be isomorphous to (Dglc)2NaCl*H2O. In contrast to solution-based methods, mechanochemistry has recently been shown to yield multi-component crystal synthesis in a matter of minutes. Furthermore, this technique


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does not require the addition of solvent, and hence adhere to many of the principles of ‘green chemistry’. Mechanochemical formation of multi-component crystals have been reported for organic, inorganic and hybrid systems. Additionally, many ICCs have been successfully obtained by this technique. While mechanochemical methods often yield the same products as by solution, the mechanisms by which they form differ considerably. Moreover, the mechanisms that underpin mechanochemical reactions can also vary. For example over an eutectic21 or amorphous phase22. Recent developments have allowed the monitoring of mechanochemical transformations in real time and in situ. This has resulted in unprecedented insight into the underlying processes that occur during mechanochemical treatment, including the presence of unexpected amorphous23 and polymorphic phases24. Despite numerous reports of ICC formation by mechanochemistry, to the best of our knowledge none have yet followed the formation of ICCs in real time and in situ. Herein, we report the in situ investigation of the mechanochemical reaction of glucose with three sodium salts (NaCl, NaBr, NaI). The formation of the ICC proceeds as a direct reaction in each case without the formation of intermediates. The crystal structures of the ICCs Glc2:NaBr (2) and Glc2:NaI (3) were solved from powder X-ray diffraction data and refined by the Rietveld method. Interestingly, hydrate formation like for the NaCl analogue (1) was not observed, but instead disorder in the halide anion position was found to occur. All ICCs were further characterized by Raman spectroscopy, elemental analysis and differential thermal analysis coupled with thermogravimetric analysis (DTA-TG). Experimental Section Materials & synthesis


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All chemicals were used as purchased without prior purification: D-(+)-glucose (Chemsolute, > 99%; Glc), NaBr (Honeywell, > 99%), NaI (abcr, 99%), methanol (Chemsolute, > 99.95%). The reactions were performed by neat grinding and liquid-assisted grinding in a vibration ball mill (Pulverisette 23, Fritsch) at 50 Hz for 1 h. The starting materials were weighed into a stainless-steel jar (10 mL) with two stainless steel balls (diameter 10 mm, 4 g). For LAG, 200 µL methanol were added before the reaction started. For the synthesis of Glc2:NaCl*H2O (1) anhydrous D-(+)-glucose (0.8612 g, 4.318 mmol, 2 eq.) and NaCl (0.1388 g, 2.158 mmol, 1 eq.) were added into a steel jar. For the formation of Glc2:NaBr (2) anhydrous glucose (0.7779 g, 4.318 mmol, 2 eq.) and NaBr (0.2221 g, 2.158 mmol, 1 eq.) were ball-milled inside the respective steel jar. Similarly, anhydrous glucose (0.7062 g, 3.920 mmol. 2 eq.) and NaI (0.2938 g, 1.960 mmol, 1 eq.) were added to a steel jar for the synthesis of Glc2:NaI (3).

Analytical techniques The dried products were characterized by powder X-ray diffraction (PXRD). Glc2:NaBr (2) was measured on the D8 Discover diffractometer (Bruker, AXS, Germany) using CuKα1 in a scanning range from 7° to 60°. A step size of 0.009° and time per step of 1728 s were chosen. The diffractogram of Glc2:NaI (3) was obtained from a D8 Advanced diffractometer (Bruker AXS, Germany) using CuKα1 and CuKα2 wavelengths. The measurement was performed in the scanning range from 7° to 60°, using a step size of 0.009o and time per step of 1728 s.


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To extract precise lattice parameters, peak profiles and intensities, Le Bail fits were performed based on the best indexing solution. Amongst the probable indexing solutions, structureless Pawley fitting was performed, using the simulated intensities of P-centered orthorhombic (P222) and trigonal (P31) lattices. This offered a good fit to the observed data. The lattice parameters derived from the trigonal solution offers the best figure of merit and comparable volume to that of known Glc2:NaCl anhydrous analogue, and were therefore chosen for further Rietveld refinement of the whole data. The background of the XRD pattern was modelled by a Chebyshev polynomial (order 9), whereas phase peak shapes were modelled by the fundamental parameter approach implemented in TOPAS 5.25 In situ PXRD measurements were performed at the μ-Spot-beamline (BESSY II, Helmholtz Centre Berlin for Materials and Energy, Germany). The set-up details were reported in our previous study.26 High resolution synchrotron PXRD patterns were recorded with an acquisition time of 30 s for each diffractogram. Scattering images were processed using the FIT2D software.27 Transformation of the scattering vector (q) to the diffraction angle 2θ for CuKα1 radiation allows the direct comparison with the results of the laboratory PXRD measurement. The syntheses were carried out in a vibration ball mill (Pulverisette 23, Fritsch, Germany) using a Perspex grinding jar.28 In situ Raman spectroscopy was performed using a Raman RXN1TM Analyzer (Kaiser optical systems, France) with an excitation wavelength of 785 nm. The spectra were collected using a contactless probe head with a spot size of 1 mm and a working distance of 6 cm. Raman spectra were recorded every 30 s with an acquisition time of 5 s for 5 accumulations.


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DTA-TG measurements were performed on a Netzsch DSC 404. The ICCs were heated at a rate of 10 K/min from 25 K to 850 K (1) and from 25 K to 800 K (2) and (3) in an open corundum crucible under air flow. Elemental analysis shows a very good match for all three products (calculated value in brackets): Glc2:NaCl*H2O: C: 32.50 % (32.9 %) H: 5.90 % (5.73 %) N: 0.00 % (0.00 %); Glc2:NaBr: C: 31.07 % (31.36 %), H: 5.22 % (5.18 %); N: 0.00 % (0.00 %); Glc2:NaI: C: 28.23 % (28.48 %); H: 4.69 % (4.70 %); N: -0.08 % (0.00 %).

Results and Discussion Characterization of Glc2:NaX (2:1) ionic cocrystals The 2:1 ionic cocrystals of glucose (glc) with sodium salts, Glc2:NaX (1-3) were synthesized mechanochemically, starting from glucose and the respective sodium salts (Figure 1). Product 1 was obtained after 1 h by neat grinding and 8 min by liquid-assisted grinding with methanol. Products 2-3 were obtained within 8 min by neat grinding and liquidassisted grinding with methanol. No other purification step was needed.

Figure 1: Scheme of the investigated reactions of glucose with different sodium salts by mechanochemistry.

The PXRD patterns of all three products and of the respective starting materials are shown in Figure 2. No reflections associated with the starting materials were observed in the final powder diffraction patterns for any of the three product phases. The diffraction pattern of Glc2:NaCl*H2O (1) is in good agreement with that simulated from the published crystal structure.29 The presence of water is further evidenced by atomic percentage calculation via elemental analysis and by slight weight loss around 100°C in the DTA-TG measurement of the ionic cocrystal Glc2:NaCl*H2O as shown in Fig. S2. Whereas in case of ionic cocrystals Glc2:NaBr and Glc2:NaI, the first kink in the respective DTA-TG measurements (Figure S3-4), appears at 200 °C, which is attributed to the glucose decomposition. Furthermore, the melting point of the respective salts was detected in each measurement (796 °C NaCl,


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733 °C NaBr, 646 °C NaI). The Raman spectra (Figure S5) of all three products are comparable. The C-H-stretching band at 2883 cm-1 appears to harden slightly upon crystallization of the product phase, which renders it unresolved in the product spectrum. Also the bands of the COH-group in the area of 750 cm-1 to 1250 cm-1 shifts to lower wavenumbers.

Figure 2: Left: PXRD patterns of Glc2:NaCl*H2O (1) and the associated reactants. Middle: PXRD patterns of Glc2:NaBr (2) and the associated reactants. Right: PXRD patterns of Glc2:NaI (3) and the respective reactants.

Both ionic cocrystals (2) and (3) crystallize in the trigonal space group P31 (Z=9) with lattice parameters of a = 16.4374(1) Å (2) and a = 16.5289(2) Å (3) and c = 17.6222(1) Å (2) and c = 17.8822(2) Å (3). Compared to Glc2:NaCl*H2O, both (2) and (3) exhibit slightly higher density and comparable volume, presumably owing to the increased mass and ionic radius of the anion in each case (see Table 1). For Rietveld refinement of the PXRD patterns of (2) and (3), initial parameters were taken from the structural coordinates of Glc2:NaCl*H2O, having first exchanged the identity of the halogen anion from Cl- to Br- or I-, respectively. To accurately determine the atomic positions of the glucose molecule and NaO6 motifs within the structure, the bond lengths and angles were restrained through penalties using different weighting schemes. There was a modest agreement between the observed and calculated intensities with slight misfit of intensities at higher values of 2. Owing to the difference in electron density between a Br- or I- anion and the lighter Cl- anion or water molecule, we observed slightly different powder patterns with pronounced diffraction maxima. As reported earlier17, disorder can


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be found at sites occupied by water molecules and chloride ions. This contributes to an equivocal electron density that is intermediate with respect to the two components at these crystallographic sites. According to Rendle and Glazier20, this should also be true for the Br and I analogues. However, careful inspections of the difference Fourier maps of the PXRD patterns of both (2) and (3) revealed that no plausible model of the experimental electron density could be obtained if the Br- and I- anions were placed jointly with a water molecule at the corresponding three independent crystallographic sites. To identify a model capable of describing the observed electron density, several approaches were tested: i) shared crystallographic sites between the halide (X = Br or I) anion with a water molecule, ii) an extra water molecule in close proximity to the halide anion, iii) modeling of thermal factors of the halide anion by employing anisotropic displacement parameters (ADP), and iv) a disorder model for the halide anions without consideration of water molecules. Models based on approaches i) and ii) were not successful, with all attempts resulting in high residual electron density around the atomic positions. In contrast, model (iii) led to excellent modeling of the observed electron density, although we note that due to an inability to obtain a three-dimensional distribution from powder diffraction data, the refinement of ADPs is generally unphysical. In model (iv) the electron density was modeled by splitting the halide anion over two individual crystallographic sites with shared occupancy. This led to an excellent agreement with the observed electron density, splitting the halide anion across two positions on either side of that obtained by method (iii). Final inspection of the difference Fourier maps in (iii) and (iv) suggests no further water molecules, and is consistent with the TGA results discussed above. Based on analysis of the Rietveld first and Fourier difference maps, the structures


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obtained from models (iii) and (iv) both appear reasonable; their comparison is shown in the ESI. The structures differ only in the slight shift in the position of the halogen atoms; single crystal X-ray diffraction experiments will be required to resolve this structural detail. Regardless, it is clear that the bromide (2) and iodide (3) cocrystals are water-free analogues of the (D-glc)2NaX family. In (1), the Na+ cations are located on three independent atomic positions, surrounded by six oxygen atoms in the form of distorted octahedra with d(Na-O) ranging from 2.384 Å to 2.481 Å and O-Na-O angle of 66° and 140.5°. The six glc molecules adopt the chair conformation, with one axial and five equatorially-bonded substituents. The mean axial bond length is d(C-O) 1.391 Å and is slightly shorter than the mean equatorial bond length of d(C-O) 1.430 Å. In addition to these major structural motifs, hydrogen bonding is observed between the OH…O and O-H…X of Glc2:NaX. The different structural units, including the halide anion, glucose and water molecules, are connected via a hydrogen bonded network. This forms a three-dimensional framework that incorporates all OH groups (Table S1). The lengths of the hydrogen bonds (O-H…O) range from 2.5714 Å to 3.3488 Å (donor-acceptor distance). The O-H…X hydrogen bonds were found to lie in the range between 3.0953 Å to 4.2012 Å (donor-acceptor distance). The crystallographic data for both ICCs were presented in Table 1. Table S3 summarizes the selected bond distances and angles of non-hydrogen atoms, whereas Table S1 and Table S3 list the selected hydrogen bond distances and angles for compound Glc2:NaBr and Glc2:NaI, respectively.


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Figure 3: Results of the structure solution of the novel cocrystals from model (iv): Crystal structure of Glc2:NaBr (2) a) viewed along the c-axis c) Coordination sphere of the sodium ion in Glc2:NaBr (2). Crystal structure of Glc2:NaI (3) b) viewed along the b- axis d) Coordination sphere of the sodium in Glc2:NaI (3) e) Rietveld refinement of the crystal structure of Glc2:NaBr (2) f) Rietveld refinement of the crystal structure of Glc2:NaI (3). Structures obtained from model (iii) are presented in the ESI.

Table 1: Crystal data and structure refinement parameters for the ionic cocrystals Glc2:NaX (X = Br (2), I (3)) top from model (iv). Glc2:NaBr

Glc2:NaI


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Molecular formula Formula weight [g/mol] Space group, Z a=b [Å] c [Å] Vol [Å3] d [g/cm3] Diffractometer /radiation type 2 range [°] Profile function No. of parameters Rp, Rbragg Rexp, Rwp GOF

NaBr(C6H12O6)2 463.22

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NaI(C6H12O6)2 510.21

P31, 9 16.43969(19) 17.6246(2) 4123.19(8) 1.679(3)

P31, 9 16.6302 (9) 17.9953(10) 4310.1(5) 1.833(2) Bruker D8Advance Bruker D8 Discover Cu-Kα1/ Kα2 (λ=0.154060 Cu-Kα1 (λ=0.154060 nm) /0.154440 nm) 5-60 5-60 Fundamental parameter approach 22 28 2.11; 2.35 2.70; 2.39 1.21; 2.90 0.86; 3.69 2.39 4.27


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Real-time in situ investigation of the three ionic cocrystals To better understand the mechanism of the milling reaction, ICC formation was followed by our tandem in situ approach. This comprises simultaneous time-resolved PXRD and Raman spectroscopy.28 The time-resolved Raman spectra are provided in the supporting information, Figure S6. The starting materials were placed into an acrylic glass jar (10 mL) with two stainless steel balls (diameter 10 mm) in a vibratory ball mill (Pulverisette 23, Fritsch, Germany) and milled at 50 Hz for 8 min. The time-resolved 2D PXRD plots are shown in Figure 4. The formation of the ICC passes via three broad phases: (1) Only starting materials (Figure 4, blue); (2) crystallization of the product alongside residual starting material (Figure 4, orange); and (3) only product (Figure 4, red). In the first stage of LAG process of (1), reflections of both starting materials are present. The first product reflections appear after only 3.5 min grinding (2 = 11°, 19°, 24°), indicating the start of stage two. At this time main reflection of sodium chloride at 2 = 31° is no longer detectable. During the second stage, reflections of glucose and of the product phase are present, with all traces of glucose disappearing by the onset of stage three (at 6.5 min grinding). At this stage, only reflections of the product are detected, and no further changes are observed in the PXRD profiles upon further grinding. The corresponding Raman spectra (Figure S6, left) indicate the end of the ICC formation process after 4.5 min. The C-H-stretching band of glucose at 2883 cm-1 appears to harden slightly upon crystallization of the product phase, is no longer visible after 4 to 5 min. The time-resolved PXRD pattern shows low intensity for the glucose reflections at this time indicating a low phase fraction of glucose. The NG process of (2) can be divided into four stages. The first stage lasts for the first two minutes of the milling process, during which reflections of both NaBr and glucose can be detected. During this stage, the main reflection of glucose at 2 = 19° decreases until it is overshadowed by the product reflection at the same scattering angle in stage two. During the second stage, both starting materials can be detected. The reflections of NaBr lose intensity as the product is formed. After 5 min, the third stage is reached. Finally, the reflections of NaBr disappeared completely and only glucose and the product can be detected in the reaction mixture. After 6.5 min, the reaction is complete, and only the product can be detected. In the Raman spectra (Figure S6), the characteristic glucose band at 2883 cm-1 is again found to be unresolved in the product spectrum and is no longer visible after 6.5 min of milling. Consistent with PXRD results, formation of the ICC Glc2:NaBr is complete after a milling time of 6.5 min. The NG process of (3) can be divided into three stages. In the first stage, reflections of glucose, NaI and the product are detected. The main reflections of NaI at 27° and 40° vanishes and are undetectable by the end of stage 1. During the second stage, reflections of the product and the product phase are detected, with all traces of glucose disappearing by the onset of stage three (at 60 s grinding). In the third stage, only reflections of the product are detected. Similarly, Raman spectra indicate an unresolved glucose band (2883 cm-1) after one minute of milling. Thus, both PXRD and Raman spectroscopy suggest the end of Glc2:NaI formation to occur after only one minute of milling.


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Figure 4. Synchrotron in situ PXRD measurements emphasizing the gradual structural evolution of new products namely; (a) Glc2:NaCl*H2O (1), (b) Glc2:NaBr (2) and (c) Glc2:NaI (3) at intermittent time intervals. The diffraction patterns of the starting materials and each product are given below and above, respectively.

Formation of all three ICCs was successfully monitored to completion by both complementary techniques. The addition of solvent in the synthesis of (1) results in formation of product prior to milling. Despite no explicit addition of solvent in the synthesis of (3), the same phenomenon is observed, but is not seen in formation of (2). Noting the relative hygroscopicities of the parent salts (NaI >> NaBr), we suggest this to be a case of inadvertent liquid assisted grinding.[30] This further suggests why the two alleged NG reactions exhibit drastically different overall reaction rates. In all syntheses the products are formed without any intermediate or amorphous phase and all products contain the 2:1 Glc2:NaX. This is presumably due to solubilization of the reactants in the liquid, and subsequent growth of the product phase. The subsequent


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mechanochemical grinding facilitates mixing, and thus accelerates the reaction (see Figure 5).

Figure 5: Schematic representation of the reaction of glucose with different sodium salts.

Conclusion In the present study three ionic cocrystals (Glc2:NaCl*H2O, Glc2:NaBr, Glc2:NaI) were successfully synthesized by mechanochemical methods. The reaction products were characterized by powder X-ray diffraction, Raman spectroscopy, DTA-TG, and elemental analysis. In addition, the reaction was investigated in situ and in real-time using a tandem approach comprising simultaneous in situ synchrotron powder X-ray diffraction and in situ Raman spectroscopy. All three ionic cocrystals are formed by the addition of two glucose molecules to the salt, without the formation of any intermediate or amorphous phase. The reaction under LAG conditions is accelerated with the prompt onset of product reflections compared to the neat grinding reaction. The crystal structures of Glc2:NaBr and Glc2:NaI were solved from powder X-ray diffraction data, confirming that both ionic compounds crystallize in the trigonal space group P31 and are isostructural to the ionic cocrystal Glc2:NaCl. The mechanochemical approach proved to be a powerful tool for the synthesis of ionic cocrystals with glucose and different salts.

ASSOCIATED CONTENT Supporting Information, Hydrogen bonding for Glc2:NaBr and Glc2:NaI, PXRD comparison for Glc2:NaCl*H2O to the literature hydrate and anhydrous structures, DTA-TG measurements, Raman spectroscopy, in situ Raman spectroscopy. AUTHOR INFORMATION Corresponding Author


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*[email protected] Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. ACKNOWLEDGMENT We are grateful for the funding received from the Excellence Initiative of the German Research Foundation (DFG project: GSC 1013) and the Graduate School of Analytical Sciences Adlershof (SALSA). We acknowledge Dr. Stefan Reinsch for DTA-TG measurements and Dr. Andrea Zehl and Mrs. Jenny Odoj for elemental analysis. ABBREVIATIONS LAG, liquid-assisted grinding, Glc, glucose; PXRD, powder X-ray diffraction; DTA-TG, Differential thermal analysis and thermogravimetric analysis; EA, elemental analysis; REFERENCES [1] S. Aitipamula; R. Banerjee; A. K. Bansal; K. Biradha; M. L. Cheney; A. R. Choudhury; G. R. Desiraju; A. G. Dikundwar; R. Dubey; N. Duggirala; P. P. Ghogale; S. Ghosh; P. K. Goswami; N. R. Goud; R. R. K. R. Jetti; P. Karpinski; P. Kaushik; D. Kumar; V. Kumar; B. Moulton; A. Mukherjee; G. Mukherjee; A. S. Myerson; V. Puri; A. Ramanan; T. Rajamannar; C. M. Reddy; N. Rodriguez-Hornedo; R. D. Rogers; T. N. G. Row; P. Sanphui; N. Shan; G. Shete; A. Singh; C. C. Sun; J. A. Swift; R. Thaimattam; T. S. Thakur; R. Kumar Thaper; S. P. Thomas; S. Tothadi; V. R. Vangala; N. Variankaval; P. Vishweshwar; D. R. Weyna; M. J. Zaworotko; Polymorphs, Salts, and Cocrystals: What’s in a Name? Crystal Growth & Design, 2012, 12 (5), 2147-2152. [2] D. Braga; L. Maini; F. Grepioni; Mechanochemical preparation of co-crystals. Chemical Society Reviews, 2013, 42 (18), 7638-7648. [3] N. K. Duggirala; M. L. Perry; Ö. Almarsson; M. J. Zaworotko; Pharmaceutical cocrystals: along the path to improved medicines. Chemical Communications, 2016, 52 (4), 640-655. [4] N. Shan; M. J. Zaworotko; The role of cocrystals in pharmaceutical science. Drug Discovery Today, 2008, 13 (9), 440-446. [5] D. Braga; F. Grepioni; O. Shemchuk; Organic–inorganic ionic co-crystals: a new class of multipurpose compounds. CrystEngComm, 2018, 20 (16), 2212-2220. [6] C. Butterhof; W. Milius; J. Breu; Co-crystallisation of benzoic acid with sodium benzoate: the significance of stoichiometry. CrystEngComm, 2012, 14 (11), 39453950.


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Page 17 of 19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


[7]

[8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23]

D. Braga; F. Grepioni; L. Maini; S. Prosperi; R. Gobetto; M. R. Chierotti; From unexpected reactions to a new family of ionic co-crystals: the case of barbituric acid with alkali bromides and caesium iodide. Chemical Communications, 2010, 46 (41), 7715-7717. N. Schultheiss; A. Newman; Pharmaceutical Cocrystals and Their Physicochemical Properties. Crystal Growth & Design, 2009, 9 (6), 2950-2967. T. Friščić; S. L. Childs; S. a. A. Rizvi; W. Jones; The role of solvent in mechanochemical and sonochemical cocrystal formation: a solubility-based approach for predicting cocrystallisation outcome. CrystEngComm, 2009, 11 (3), 418-426. R. P. Rastogi; N. B. Singh; Solid-state reactivity of picric acid and substituted hydrocarbons. The Journal of Physical Chemistry, 1968, 72 (13), 4446-4449. K. Chadwick; R. Davey; W. Cross; How does grinding produce co-crystals? Insights from the case of benzophenone and diphenylamine. CrystEngComm, 2007, 9 (9), 732-734. A. Jayasankar; A. Somwangthanaroj; Z. J. Shao; N. Rodríguez-Hornedo; Cocrystal Formation during Cogrinding and Storage is Mediated by Amorphous Phase. Pharmaceutical Research, 2006, 23 (10), 2381-2392. M. Calloud; Mémoires de la Société Académique de Savoie 1, 1825, 34. C. H. Gill; XVI.—On some saline compounds of cane-sugar. Journal of the Chemical Society, 1871, 24 (0), 269-275. M. Shinnosuke; ÜBER DAS GLEICHGEWICHT DES SYSTEMS GLUKOSE-KOCHSALZWASSER. Bulletin of the Chemical Society of Japan, 1927, 2 (2), 44-48. K. C. Wong; A. Hamid; S. Baharuddin; C. K. Quah; H.-K. Fun; catena-Poly[[sodium-diμ-β-d-glucose] chloride]. Acta Crystallographica Section E: Structure Reports Online, 2009, 65 (Pt 11), m1308-m1309. G. Ferguson; B. Kaitner; B. E. Connett; D. F. Rendle; Structure of the [alpha]-dglucose-sodium chloride-water complex (2/1/1). Acta Crystallographica Section B, 1991, 47 (4), 479-484. J. Stenhouse; XXXV.—Note on a compound of dextro-glucose with bromide of sodium. Journal of the Chemical Society, 1863, 16 (0), 297-299. H. Oertling; Interactions of alkali- and alkaline earth-halides with carbohydrates in the crystalline state – the overlooked salt and sugar cocrystals. CrystEngComm, 2016, 18 (10), 1676-1692. D. F. Rendle; E. J. Glazier; X-Ray Powder Diffraction Data for Complexes of Glucose Monohydrate with Sodium Bromide and Sodium Iodide. Powder Diffraction, 1992, 7 (1), 38-41. K. Chadwick; R. Davey; W. Cross; How does grinding produce co-crystals? Insights from the case of benzophenone and diphenylamine. 2007; Vol. 9. A. Jayasankar; A. Somwangthanaroj; Z. J. Shao; N. J. P. R. Rodríguez-Hornedo; Cocrystal Formation during Cogrinding and Storage is Mediated by Amorphous Phase. 2006, 23 (10), 2381-2392. I. Akhmetova; K. Schutjajew; M. Wilke; A. Buzanich; K. Rademann; C. Roth; F. J. J. O. M. S. Emmerling; Synthesis, characterization and in situ monitoring of the mechanochemical reaction process of two manganese(II)-phosphonates with Ncontaining ligands. 2018, 53 (19), 13390-13399.


17


[24] [25] [26]

[27] [28] [29]

Page 18 of 19

H. Kulla; S. Greiser; S. Benemann; K. Rademann; F. Emmerling; Knowing When To Stop—Trapping Metastable Polymorphs in Mechanochemical Reactions. Crystal Growth & Design, 2017, 17 (3), 1190-1196. Brukeraxs; 2014. O. Paris; C. Li; S. Siegel; G. Weseloh; F. Emmerling; H. Riesemeier; A. Erko; P. Fratzl; A new experimental station for simultaneous X-ray microbeam scanning for smalland wide-angle scattering and fluorescence at BESSY II. Journal of Applied Crystallography, 2007, 40 (s1), s466-s470. A. P. Hammersley; S. O. Svensson; M. Hanfland; A. N. Fitch; D. Hausermann; Twodimensional detector software: From real detector to idealised image or two-theta scan. High Pressure Research, 1996, 14 (4-6), 235-248. L. Batzdorf; F. Fischer; M. Wilke; K.-J. Wenzel; F. Emmerling; Direct In Situ Investigation of Milling Reactions Using Combined X-ray Diffraction and Raman Spectroscopy. Angewandte Chemie International Edition, 2015, 54 (6), 1799-1802. D. F. Rendle; B. E. Connett; Characterization of a glucose monohydrate/sodium chloride complex by X-ray diffraction methods. Journal of the Forensic Science Society, 1988, 28 (5), 295-297.

[30] I.A. Tumanov, A.A.L. Michalchuk, A.A.Politov, E.V. Boldyreva and V.V. Boldyrev, Inadvertent liquid assisted grinding: a key to ‘dry’ organic mechano-co-crsytallisation?, CrystEngComm, 2017, 21, 2820-2835


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For Table of Contents Use Only:

We describe the mechanochemical synthesis of the ionic cocrystals of glucose (Glc) and sodium salts Glc2NaCl*H2O (1) and Glc2NaX (X = Br (2), I (3)). The formation pathways were elucidated using timeresolved in situ Synchrotron X-ray diffraction.


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A Comparative Study of the Ionic Cocrystals NaX - ACS Publications

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