Phenylacetic acid co-crystals with acridine, caffeine, isonicotinamide and nicotinamide: Crystal structures, thermal analysis, FTIR spectroscopy and Hirshfeld surface analysis

Accepted Manuscript Phenylacetic acid co-crystals with acridine, caffeine, isonicotinamide and nicotinamide: Crystal structures, thermal analysis, FTIR spectroscopy and Hirshfeld surface analysis Francoise M. Amombo Noa, Ayesha Jacobs PII:

S0022-2860(17)30224-7

DOI:

10.1016/j.molstruc.2017.02.066

Reference:

MOLSTR 23460

To appear in:

Journal of Molecular Structure

Received Date: 29 November 2016 Revised Date:

15 February 2017

Accepted Date: 15 February 2017

Please cite this article as: F.M. Amombo Noa, A. Jacobs, Phenylacetic acid co-crystals with acridine, caffeine, isonicotinamide and nicotinamide: Crystal structures, thermal analysis, FTIR spectroscopy and Hirshfeld surface analysis, Journal of Molecular Structure (2017), doi: 10.1016/j.molstruc.2017.02.066. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Department of Chemistry, Faculty of Applied Sciences, Cape Peninsula University of Technology, PO

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Box 652, Cape Town, 8000, South Africa

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Francoise M. Amombo Noaa, Ayesha Jacobsa, ∗

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Phenylacetic acid co-crystals with acridine, caffeine, isonicotinamide and nicotinamide: crystal structures, thermal analysis, FTIR spectroscopy and Hirshfeld surface analysis

——— ∗ Ayesha Jacobs. Tel.: +27-21-460-3167; e-mail: [email protected]

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Graphical Abstract

Phenylacetic acid co-crystals with acridine, caffeine, isonicotinamide and nicotinamide: crystal structures, thermal analysis, FTIR spectroscopy and Hirshfeld surface analysis

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Journal of Molecular Structure journal homepage: www.elsevier.com

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Phenylacetic acid co-crystals with acridine, caffeine, isonicotinamide and nicotinamide: crystal structures, thermal analysis, FTIR spectroscopy and Hirshfeld surface analysis Francoise M. Amombo Noaa, Ayesha Jacobsa, ∗ a

Department of Chemistry, Faculty of Applied Sciences, Cape Peninsula University of Technology, PO Box 652, Cape Town, South Africa

ABSTRACT

Article history: Received Received in revised form Accepted Available online

Co-crystals of phenylacetic acid (PAA) with acridine (ACR), caffeine (CAF), isonicotinamide (INM) and nicotinamide (NAM) have been successfully prepared and characterised by single crystal X-ray diffraction, FTIR spectroscopy, thermal analysis and Hirshfeld surface analysis. The ACR, INM and NAM co-crystals with PAA exhibit the carboxylic acid-pyridine heterosynthon. Furthermore the amide-amide supramolecular homosynthon is observed in the PAA co-crystals with INM and NAM as well as N-H···O interactions between the acid and the respective base. The CAF co-crystal exhibits hydrogen bonding between the imidazole nitrogen and the COOH group of the PAA. The compounds demonstrate different stoichiometries; for PAA·ACR and PAA·INM a 1:1 ratio is displayed, a 2:1 in 2PAA·CAF and a 2:2 in the case of 2PAA·2NAM.

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Keywords: Phenylacetic acid Co-crystals Caffeine Acridine Nicotinamide

1. Introduction

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Many techniques have been reported on how co-crystal formers can be combined to form new crystalline materials [1-6]. Neat and solvent drop grinding, slurry conversion and solution crystallisation are some examples of these techniques. This has resulted in an increase in the number of articles dealing with the preparation of co-crystals and salts using solid-state techniques [7-9]. The formation of salts or co-crystals can enhance physicochemical properties of drugs such as solubility and bioavailability [10-13]. We recently reported co-crystals of vanillic acid [14] successfully prepared via slurry conversion experiments and liquid assisted grinding. These techniques are also used to obtain different polymorphic forms [15-18]. These new crystalline forms can further be characterised using techniques such as FTIR spectroscopy which can indicate whether the new complex formed is a co-crystal or a salt [19-24], and Hirshfeld surface analysis for a better understanding of the non-bonded interactions in the crystal structures [25]. In this study, phenylacetic acid (PAA) co-crystals were prepared with acridine (ACR), caffeine (CAF), isonicotinamide (INM) and nicotinamide (NAM). The cocrystals were characterized using single and powder X-ray diffraction, FTIR spectroscopy and thermal analysis. Hirshfeld surface analysis was performed on the obtained

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ARTICLE INFO

2016 Elsevier Ltd. All rights reserved.

co-crystals and the resultant fingerprint plots were compared. Alternate methods of preparation of the new compounds; PAA·ACR, 2PAA·CAF, PAA·INM and 2PAA·2NAM were explored using neat-grinding, liquid assisted grinding and slurry conversion besides the conventional method of solvent crystallisation. Single crystal X-ray diffraction was utilised for the identification of hydrogen bonding patterns. All of the co-crystal formers contain nitrogen and our interest was to exploit the COOH···N supramolecular heterosynthon to form new compounds. The most frequently observed example of this type is the carboxylic acid-pyridine (COOH···Npyr) synthon which has been the subject of several studies [26-29]. The COOH···N heterosynthon competes with the acid-acid homosynthon in the formation of the new multicomponent crystal. Benzoic acid and its derivatives are often used in case studies of this nature. In our study PAA was chosen as the target compound. PAA has more flexibility than benzoic acid due to the additional –CH2 which results in a non-planar conformation of the acid [30]. Co-crystals of PAA with 2-pyridone [31], 3-pyridinealdazine [32], 4pyridinealdazine [33], benzamide [34], 1-(carboxymethyl) pyridine [19], hexamethylenetetramine [35], a salt co-crystal hydrate with adenine [36] and salts with Cinchona alkaloids [37] have been reported in the CSD (November 2015, May 2016 update) [38]. Co-ordination polymers of PAA

∗ Corresponding author. Tel.: +27-21-460-3167; e-mail: [email protected]

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2.3. Powder X-ray diffraction involving cobalt and zinc, [39] a chromium complex [40] MANUSCRIPT ACCEPTED and a potassium salt [41] of PAA are also known. The Powder XRD patterns of all samples were recorded using a schematic representation of PAA and co-formers is shown D2 Phaser Bruker diffractometer with Cu-Kα radiation of in Scheme 1. 1.54184 Å. Each sample was scanned between 4 - 50° 2θ, with the voltage tube and amperage at 30 kV and 10 mA max, respectively using an Xflash detector and a scintillation counter, 1-dim LYNXEYE. 2.4. Infrared spectroscopy

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Infrared spectra were recorded on a Perkin-Elmer FTIR 1000 spectrophotometer utilizing a KBr diffuse – reflectance mode (1 mg of sample in 250 mg of KBr), which allowed the collection of the infrared spectra of samples. The spectra were taken over the range of 4000 – 400 cm-1 at a 2 cm-1 spectral resolution. 2.5. Thermal analysis

2. Experimental

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Scheme 1. Phenylacetic acid and co-formers used in this study.

Samples utilized for differential scanning calorimetry (DSC) were crushed and placed in crimped and vented pans. DSC analyses were performed on a Perkin-Elmer 6 system with a purge of nitrogen at 20 ml min-1. These analyses were conducted from 303 – 600 K with a heating rate of 10 K min-1. 3. Results and discussion

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3.1. Structural analysis

All chemicals were purchased from Sigma – Aldrich and used as received.

The crystallographic data parameters of the PAA co-crystals are given in Table 1.

2.1. Preparation of PAA co-crystals

Co-crystal 1 between PAA and ACR was solved in the space group PĪ and exhibited the preferred COOH···N hydrogen bond (Fig.1) with an O···N distance of 2.687 (2) Å and a CH···O interaction with d (C···O) = 3.326 (2) Å. Only the hydrogens involved in hydrogen bonding are indicated on the diagram and this approach was followed in all subsequent figures. These

1, PAA·ACR. PAA (50 mg, 0.367 mmol) and ACR (65.82 mg, 0.367 mmol) were dissolved in diethyl ether. The clear solution was allowed to evaporate for a few days to give block-like yellow-orange crystals.

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2, 2PAA·CAF. PAA (50 mg, 0.367 mmol) and CAF (71.31 mg, 0.367 mmol) crystallised from a 50/50 (v/v) chloroform/methanol mixture. Needle-like crystals were obtained after a few days. Similar crystals were also obtained using distilled water as a solvent.

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3, PAA·INM. PAA (50 mg, 0.367 mmol) and INM (44.85 mg, 0.367 mmol) were dissolved in ethyl methyl ketone. The solution was allowed to evaporate at ambient temperature and plate-like crystals were obtained after a few days.

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4, 2PAA·2NAM. PAA (50 mg, 0.367 mmol) and NAM (44.85 mg, 0.367 mmol) were dissolved in acetone. The solution was allowed to evaporate and needle-like crystals were obtained after a few days. Similar crystals were also obtained using ethyl methyl ketone as a solvent.

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hydrogen bonds form a ring which can be described as R 2 (8). The structure is further stabilised by π···π (shortest distance of 3.736 Å) and C-H···π interactions. Comparison of structure 1 to that of the 1:1 structure of acridine and benzoic acid (BA) [47] indicates the presence of the COOH···N hydrogen bond with d (O···N)= 2.668 (2) Å however there is an absence of the CH···O interaction. Adjacent ACR molecules interact by π···π stacking with a distance of 3.736 Å. However the packing of the two structures are different in that distinct layers of PAA and ACR molecules are present in 1 and this is not the case for the BA·ACR.

2.2. Structure analysis

Good quality single-crystals of 1 – 4, were selected for the Xray diffraction experiments at 173 (2) K. Their cell dimensions were established from intensity data measured on a Bruker DUO APEX II diffractometer [42] using Mo Kα radiation (λ = 0.71073 Å), and collected by the phi scan and omega scan techniques, which were scaled and reduced with SAINT-Plus [43]. The correction of the collected intensities for absorption was done using SADABS [44]. The structures were solved by direct methods using SHELX-97 [45] and refined using full-matrix least squares methods in SHELXL [45]. The graphical interface used was X-SEED [46]. All non-hydrogen atoms were refined anisotropically. The hydrogen atoms were placed geometrically with a riding model for their isotropic temperature factors except for those involved in hydrogen bonding which were found in the electron density map and refined isotropically.

Fig. 1. Hydrogen bonding in PAA·ACR showing the heterosynthon.

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Co-crystal 2 (2PAA·CAF), solved in P21/c with PAA and CAF MANUSCRIPT ACCEPTED located in general positions. The asymmetric unit contains one CAF and two PAA molecules. The hydrogen bonding in 2 (Fig. 2) is via (PAA) O-H···O (PAA) with an O···O distance of 2.690 (2) Å and (PAA) O-H···N (CAF) with an O···N distance of 2.670 (2) Å. There are also C-H···O interactions of 3.160 (2) Å and 3.291 (2) Å respectively. This connection shows ring motifs of 2

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crystal was elusive for decades and could not be obtained through conventional techniques. A 1:1 CAF:BA co-crystal was obtained by heteronuclear seeding using various CAF and fluorobenzoic acid co-crystals as seeds [48]. CAF·BA also crystallised in P21/c with a hydrogen bond involving the imidazole nitrogen and the carboxylic acid [d(O···N) = 2.663 (7) Å as well as a C-H···O interaction between CAF and BA.

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R 2 (7) and R 3 (11). Interestingly the caffeine: benzoic acid co-

Fig. 3. Hydrogen bonding between INM and PAA molecules.

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The crystal structure of 2PAA·2NAM (4) was solved in the space group P21/n. The hydrogen bonding pattern is comparable to that found in 3 in that the co-crystal structural network (Fig. 4) occurs 2

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via the hydrogen bonded R 2 (8) ring motif between two NAM molecules [d(N···O), 2.885 (2) Å]. The amide-amide dimers are connected via COOH···Npyr [d(O···N) = 2.604 (2) Å] and N-H···O 2

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[d(N···O) = 2.973 (2) Å] hydrogen bonds which form C 2 (10) chains along [010]. The same interaction occurs for the second NAM molecule in the asymmetric unit [d (N···O) = 2.878 (2) Å] with COOH···Npyr [d(O···N) = 2.606 (2) Å] and N-H···O [d(N···O) = 3.038 (2) Å].

Fig. 2. Hydrogen bonding in 2PAA·CAF.

The primary synthons in the PAA/INM co-crystal (3) obtained in ethyl methyl ketone are the COOH···Npyr [d (O···N), 2.629 (2) Å], and also N-H···O connections between two INM molecules [d (N···O) = 2.896 (2) Å] to form a dimer which can be described as

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R 2 (8) [49] shown in Fig. 3. The amide-amide homosynthon and the COOH···Npyr are further connected via an N-H···O [d (N···O) 2

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= 2.961 (1) Å] hydrogen bond to form C 2 (11) chains. There are two reported co-crystals formed between INM and BA which differ in stoichiometry. A 1:1 co-crystal reported by Aakeröy et 2

al [50] also displayed the R 2 (8) hydrogen bonded ring via a selfcomplementary amide···amide interaction. This co-crystal was also hydrogen bonded by O-H···N interactions and exhibited 2 C2

(11) chains. The second INM/BA co-crystal, a 2:1 complex consists of two independent three-component fragments [51, 52]. One BA is bound to the pyridine nitrogen of INM through an OH···N bond while the second BA forms O-H···N and N-H···O 2

hydrogen bonds with the INM amide group to form a R 2 (8) hydrogen bond pattern. Thus PAA·INM has a similar hydrogen bonding motif to that of the 1:1 BA·INM. Both of these structures contain the amide-amide homosynthon in contrast to the 2:1 BA·INM which contains the acid-amide heterosynthon.

Fig. 4. Hydrogen bonding in 4, along [010].

3.2. Grinding Experiment The four co-crystals of PAA were also characterised using powder X-ray diffraction. All the PXRD analyses of the products of the neat-grinding, liquid assisted grinding and slurry conversion experiments conducted to prepare 1 were in excellent agreement with the calculated PXRD pattern obtained from LAZYPULVERIX [53]. Slurry conversion and liquid assisted grinding performed in 50/50 (v/v) chloroform/methanol were the experiments that yielded the same PXRD’s patterns as 2. The neat ground product after 20 and 30 minutes did not completely match the calculated pattern from LAZYPULVERIX [53] as there were still some residual peaks due to the starting materials. Ground products after 30 and 40 minutes for 3 matched the PXRD pattern of the slurry, which did not match the physical

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3.3. Infrared spectroscopy

Fig. 5. DSC traces of 2PAA·CAF (red), CAF (green) and PAA (blue). Table 2. DSC results of PAA co-crystals and starting materials. Compound

However, a salt is obtained when the free acid band completely disappears and is replaced by an anion band which ranges from 1550 cm-1 – 1600 cm-1.

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3.4. Thermal analysis

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In the case of 1, the C=O band occurs at 1698 cm-1 which is similar to that found in PAA (1699 cm-1). Thus the pattern of molecular motion of the supramolecular synthon is not significantly different to those of the initial reactants. For cocrystal 2, the IR spectrum of the physical mixture contains C=O bands at 1710, 1698 and 1662 cm-1 compared to the slurry product of the co-crystal which were shifted to lower frequencies (1700, 1678 and 1644 cm-1). Co-crystals 3 and 4 demonstrated the presence of new bands (3369 and 3158 cm-1 for 3; and 3385 and 3160 cm-1 for 4) which can be assigned to H-bonded NH2 stretching modes. The lack of shift in the vibrational frequencies for the C-N stretch and N-H bends in both co-crystals (1399 cm-1 in 3 and 1408 cm-1 in 4), indicates that the force constants of the homosupramolecular synthons (ie INM (or NAM) and PAA) are not strongly changed upon formation of the co-crystal [54].

DSC results are given in Table 2 (See supporting information for the DSC curves). All co-crystals (2, 3 and 4) gave one endothermic peak, except for 1 which gave rise to two endothermic peaks in the DSC trace. A typical DSC trace is illustrated in Fig. 5 showing the DSC of PAA, CAF and the cocrystal 2PAA•CAF.

DSC Endotherm 1 (K) 363.5 331.7 419.6 382.1 -

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PAA ACR PAA·ACR CAF 2PAA•CAF INM PAA•INM NAM 2PAA•2NAM

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The main hydrogen bonding functional group in PAA is the acid moiety. IR spectroscopy was utilised to depict the carbonyl stretch (C=O) of the co-crystal which generally appears between 1650-1700 cm-1. A study of vibrational spectroscopic selection rules for the identification of co-crystals and salts was conducted by Brittain, using 1: 1 co-crystal products of sodium salt formations of benzoic acid, phenylacetic acid, hydrocinnamic acid and 4-phenylbutanoic acid [54]. The results illustrated that the free acid absorption band occurs in the frequency range of 1680 cm- 1 – 1690 cm-1. The formation of a co-crystal occurs when there is a small shift in the free acid absorption bands towards higher energy; ranging from 1700 cm-1 to 1730 cm-1.

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mixture. However, these three PXRD patternsACCEPTED have some peaks MANUSCRIPT which are similar to the calculated pattern, with the exception of the first peak at 2θ (approximately 6.63° in the calculated pattern). Thus neat grinding and slurry experiments gave incomplete reactions. There is a peak at 2θ (approximately 4.70°) in the liquid assisted ground product which is missing in the calculated pattern of 3 and which could not be identified. The same findings in 3 were obtained in the slurry and ground experiments in 4. However the liquid assisted ground product was in overall agreement with the calculated pattern of 4.

DSC Endotherm 2 (K) 351.8 375.8 452.7 508.4 359.9 428.4 363.1 401.6 344.5

3.5. Hirshfeld surface analysis

An analysis of the non-bonded interactions in all the four cocrystals was conducted using CrystalExplorer [57,58] to obtain an insight into the difference in the thermal behaviour of the cocrystals. Fingerprint plots of each PAA molecule was generated (Fig 6) and the % contribution due to each interaction was determined and is summarized in the supplementary data. These results were compared to the DSC findings, as melting point can be influenced by intermolecular interactions [59]. The DSC results showed the trend: PAA·INM (363.1 K) > 2PAA·CAF (359.9 K) > 2PAA·2NAM (344.5 K) > PAA·ACR (331.7 K). The melting point results correlate with the % contributions from the stronger hydrogen bonds ie. the O···H and N···H interactions. The % O···H and N···H contributions can be summarized: PAA·INM (24.5%; 3.8%) > 2PAA·CAF (24.2%; 1.7%) > 2PAA·2NAM (19.7%; 4.6%) > PAA·ACR (21.1%; 2.8%). The structures are dominated by H···H interactions which ranges from 46.0% for PAA•INM to 55.9% for PAA·ACR. There are also significant C···H interactions due to the aromatic nature of the PAA and the co-crystal formers ranging from 14.8% for PAA·ACR to 24.3% for 2PAA•2NAM. In contrast, notable C···C contacts were only found for PAA·ACR (4.6%) and PAA•INM (4.1%).

PAA·ACR shows a decrease in thermal stability [55, 56] of the co-crystal which is due to its low melting point compared to the starting components (Table 2). The melting point of 2PAA•CAF was found to be in-between the two starting material’s melting points. This implies that the co-crystal has a higher thermal stability than the PAA compound and a lower thermal stability than caffeine. The melting point of PAA•INM was found to be in-between the two components as in 2. The melting point of the 2PAA•2NAM co-crystal was found to be lower than both PAA and NAM. This indicates that there is a decrease in the thermal stability of the co-crystal. Fig. 6. 2D fingerprint plots of (a) PAA·ACR, (b) 2PAA·CAF (PAA molecule 1), (c) 2PAA·CAF (PAA molecule 2), (d) PAA•INM, (e) 2PAA•2NAM (PAA molecule 1) and (f) 2PAA•2NAM (PAA molecule 2). The spikes labelled 1-4 show the O···H, H···H, C···H and N···H interactions respectively.

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Phenylacetic acid co-crystals were prepared with acridine, caffeine, isonicotinamide and nicotinamide. All of the structures are dominated by the COOH···N synthon which indicates the importance of this interaction in the formation of the co-crystals under investigation. For PAA·ACR the COOH···Npyr was present as well as a C-H···O interaction. Both PAA•INM and 2PAA•2NAM displayed the amide-amide homosynthon, COOH···Npyr and N-H···O contacts. For 2PAA·CAF the COOH···Nimidazole was found in addition to a C-H···O interaction. The thermal stability of the co-crystals was determined using DSC and it was found that the melting points of the co-crystals were either lower or in-between those of the starting materials. Furthermore a correlation was established between the melting points of the co-crystals and the O···H and N···H interactions with the PAA•INM showing the highest thermal stability and PAA·ACR the least stable. PAA·ACR was also successfully prepared using neat-grinding, liquid assisted grinding and slurry experiments. Slurry conversion and liquid assisted grinding successfully resulted in 2PAA·CAF. These alternate methods of preparation were only partially successful in the case of PAA•INM and 2PAA•2NAM with the nicotinamide co-crystal successfully prepared using liquid assisted grinding.

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4. Conclusion

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Table 1. Crystallographic data and structure refinement parameters of PAA co-crystals.

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3

4

PAA·ACR

2PAA·CAF

PAA·INM

2PAA·2NAM

C8H8O2·C13H9N

2C8H8O2·C8H10N4O2

C8H8O2·C6H6N2O

2C8H8O2·2C6H6N2O

Molecular mass (g mol-1)

315.36

466.49

258.27

516.54

Data collection temp. (K)

173 (2)

173 (2)

173 (2)

173 (2)

Crystal size (mm)

0.08×0.10×0.12

0.06×0.18×0.46

0.06×0.09×0.13

0.09×0.20×0.45

Space group

P1 7.7375 (15)

C2/c

P21/n

32.264 (7)

12.389 (3)

6.6629 (6)

4.3278 (9)

5.0838 (10)

23.183 (2)

22.602 (5)

41.803 (8)

90

90

90

102.338 (2)

125.10 (3)

95.79 (3)

90

90

90

2259.1 (3)

2582.1 (14)

2619.5 (10)

4

8

4

1.372

1.329

1.310

0.100

0.095

0.094

1.80-27.14

1.54-28.36

1.68-26.41

8086

11038

11688

Structural formula

a (Å) b (Å)

8.8544 (18)

c (Å)

12.457 (3)

α (°)

85.72 (3)

β (°)

85.73 (3)

γ (°)

P21/c

14.9707 (12)

794.1 (3)

Z

2 -3

Dc, calc density (g cm )

1.319 -1

Absorption coefficient (mm ) θ range

0.085 1.64-28.37

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Volume (Å )

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69.11 (3) 3

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Co-crystal

6914

No data I >2 sigma (I)

3043

3122

2644

3473

Final R indices [I >2 sigma (I)]

R1= 0.0415; wR2= 0.1049

R1= 0.0489; wR2= 0.1112

R1= 0.0361; wR2= 0.0956

R1= 0.0518; wR2= 0.1145

R indices (all data)

R1= 0.0568; wR2= 0.1148

R1= 0.0904; wR2= 0.1296

R1= 0.0457; wR2= 0.1030

R1= 0.0836; wR2= 0.1288

1.047

1.010

1.032

1.018

1519691

1519692

1519694

1519693

2

Goodness-of-fit on F CCDC no.

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Reflections collected

15. K. Chadwick, ACCEPTED MANUSCRIPT

References and notes 1.

2.

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4.

N. Shan, F. Toda, W. Jones, Mechanochemistry and cocrystal formation: effect of solvent on reaction kinetics, Chem. Comm. (2002) 2372-2373.

5.

A.V. Trask, W. Jones, Crystal engineering of organic cocrystals by the solid-state grinding approach, Top. Curr. Chem. 254 (2005) 41-70.

7.

A.V. Trask, N. Shan, W.D.S. Motherwell, W. Jones, S. Feng, R. B. H. Tan, K.J . Carpenter, Selective polymorph transformation via solvent-drop grinding, Chem. Comm. (2005) 880-882. S. Karki, T. Friščić, W. Jones, Control and interconversion of cocrystal stoichiometry in grinding: stepwise mechanism for the formation of a hydrogenbonded cocrystal, CrystEngComm. 11 (2009) 470-481.

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17. A. Mukherjee, S. Tothadi, S. Chakraborty, S. Ganguly, G.R. Desiraju, Synthon identification in co-crystals and polymorphs with IR spectroscopy. Primary amides as a case study, CrystEngComm. 15 (2013) 4640-4654. 18. P. Vishweshwar, J.A. McMahon, M.L. Peterson, M.B. Hickey, T.R. Shattock, M.J. Zaworotko, Crystal engineering of pharmaceutical co-crystals from polymorphic active pharmaceutical ingredients, Chem. Comm. (2005) 4601-4603. 19. Z. Dega-SZafran, M. Jaskólski, M. Szafran, OHO hydrogen bond and electrostatic interactions in a complex of pyridine betaine with phenylacetic acid studied by Xray diffraction, FTIR spectroscopy and PM3, DFT calculations, J. Mol. Struct. 555 (2000) 191-201. 20. G. Bruni, M. Maietta, V. Berbenni, M. Bini, S. Ferrari, D. Capsoni, M. Boiocchi, C. Milanese, A. Marini, Preparation and characterization of carprofen co-crystals CrystEngComm. 14 (2012) 435-445.

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16. D. Rossi, T. Gelbrich, V. Kahlenberg, U.J. Griesser, Supramolecular constructs and thermodynamic stability of four polymorphs and a co-crystal of pentobarbital (nembutal), CrystEngComm. 14 (2012) 2494-2506.

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We thank the National Research Foundation (South Africa) and the Cape Peninsula University of Technology.

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Acknowledgments

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R. Davey. G. Sadiq, W. Cross, R. Pritchard, The utility of a ternary phase diagram in the discovery of new co-crystal forms CrystEngComm. 11 (2009) 412-414.

D. Braga, S.L. Gaffreda, K. Rubini, F. Grepioni, M.R. Chierotti, R. Gobetto, Making crystals from crystals: three solvent-free routes to the hydrogen bonded cocrystal between 1,1′-di-pyridyl-ferrocene and anthranilic acid, CrystEngComm. 9 (2007) 39-45.

9.

P.P. Bag, M. Patni, C.M. Reddy, A kinetically controlled crystallization process for identifying new co-crystal forms: fast evaporation of solvent from solutions to dryness, CrystEngComm. 13 (2011) 5650-5652.

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ACCEPTED MANUSCRIPT

Highlights Four co-crystals of phenylacetic acid with N-containing compounds were prepared.

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Crystal structures, thermal stability and FTIR spectra are presented.

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The main synthon found in all of the structures is the COOH∙∙∙N heterosynthon.

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The thermal stability and the O∙∙∙H and N∙∙∙H interactions can be correlated.

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Grinding and slurry experiments were also investigated.

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