Synthesis, characterization and Hirshfeld surface analysis of 2-aminobenzothiazol with 4-fluorobenzoic acid co-crystal European Journal of Chemistry 13 (2) (2022) 206-213 European Journal of Chemistry ISSN 2153-2249 (Print) / ISSN 2153-2257 (Online) – Copyright © 2022 The Authors – Atlanta Publishing House LLC – Printed in the USA. This work is published and licensed by Atlanta Publishing House LLC – CC BY NC – Some Rights Reserved. https://dx.doi.org/10.5155/eurjchem.13.2.206-213.2234 European Journal of Chemistry View Journal Online View Article Online Synthesis, characterization and Hirshfeld surface analysis of 2-aminobenzothiazol with 4-fluorobenzoic acid co-crystal Bubun Banerjee 1, Varun Sharma 2, Aditi Sharma 1, Gurpreet Kaur 1 and Vivek Kumar Gupta 2,* 1 Department of Chemistry, Akal University, Talwandi Sabo, Bathinda, Punjab-151302, India 2 Department of Physics, University of Jammu, Jammu Tawi-180006, India * Corresponding author at: Department of Physics, University of Jammu, Jammu Tawi-180006, India. e-mail: vivek.gupta2k9@gmail.com (V.K. Gupta). 10.5155/eurjchem.13.2.206-213.2234 Received: 02 March 2022 Received in revised form: 14 April 2022 Accepted: 26 April 2022 Published online: 30 June 2022 Printed: 30 June 2022 The co-crystal of 2-aminobenzothiazol with 4-fluorobenzoic acid were synthesized and characterized by elemental analyses, spectral studies (FT-IR, NMR, HRMS) and single-crystal X-ray diffraction analysis. This compound co-crystallizes in the monoclinic space group P21/c (no. 14), a = 11.7869(14) Å, b = 4.0326(5) Å, c = 27.625(3) Å, β = 92.731(10)°, V = 1311.6(3) Å3, Z = 4, T = 293(2) K, μ(CuKα) = 2.345 mm-1, Dcalc = 1.470 g/cm3, 3568 reflections measured (7.508° ≤ 2Θ ≤ 134.202°), 2280 unique (Rint = 0.0262, Rsigma = 0.0413) which were used in all calculations. The final R1 was 0.0446 (I > 2σ(I)) and wR2 was 0.1274 (all data). The crystal structure is stabilized by elaborate system of N–H···O and O-H···O hydrogen bonds to form supramolecular structures. Furthermore, the 3D Hirshfeld surfaces and the associated 2D fingerprint plots have been analyzed for molecular interactions. Co-crystal X-ray diffraction Hirshfeld surface Hydrogen bonding 4-Fluorobenzoic acid 2-Aminobenzothiazol Cite this: Eur. J. Chem. 2022, 13(2), 206-213 Journal website: www.eurjchem.com 1. Introduction Easy and smooth delivery of the active pharmacological ingredient is one of the important parts of drug development. Most of the cases, the active pharmacological ingredients are crystalline solids at ambient temperature and are generally provided as a tablet form [1]. It is well established that the efficacy of a drug molecule depends on its physical properties such as dissolution rate, solubility, melting point, color etc. which again varies depending upon the packing of its crystal [2]. Co-crystallization offers significant benefit by delivering two or more different active pharmacological ingredients at a time, which in many occasions provides better efficacy than the individual single component [3]. Since the first formation of co- crystal between nucleic bases [4], these were recognized as valuable materials and gained significant attention [5-8]. These were reported to use as pharmaceutical materials [9,10], electronic and optical materials [11,12] and even employed as media for conducting solid-state organic syntheses [13-16]. Benzothiazole (Benzo[d]thiazol) is an important class of fused heterocyclic scaffold having broad range of pharmaceu- tical applications such as antimicrobial [17], anti-inflammatory [18], anticancer activities [19,20], neuroprotective [21], anti- helmintic [22], anticonvulsant [23], antiglutamate [24], anti- malarial [25], antitubercular [26] and so on. Figure 1 represents a glimpse of drug molecules having benzothiazole as the core skeleton [27]. Very recently, we have reported the X-ray diffraction analysis of a co-crystal formed between 2-aminobenzothiazol and 1-methylisatin [28]. In continuation of our strong interest towards the crystal structure of bioactive organic molecules [29-40], in this communication, we want to report the detailed X-ray diffraction analysis along with FT-IR, NMR, and HRMS studies of another co-crystal (III) formed between 4-fluoro benzoic acid and 2-aminobenzothiazol. We strongly believe that co-crystallization of these two highly active pharmacological ingredients will surely make some impact and show high therapeutic potentials. Screening of biological activities of this co-crystal is under process which will be communicated later on. 2. Experimental 2.1. General Infrared spectra were recorded on Agilent (Cary 660) FT-IR spectrophotometer on KBr discs. ABSTRACT RESEARCH ARTICLE KEYWORDS https://dx.doi.org/10.5155/eurjchem.13.2.206-213.2234 https://www.eurjchem.com/ https://dx.doi.org/10.5155/eurjchem.13.2.206-213.2234 mailto:vivek.gupta2k9@gmail.com http://www.eurjchem.com/ https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.13.2.206-213.2234&domain=pdf&date_stamp=2022-06-30 Banerjee et al. / European Journal of Chemistry 13 (2) (2022) 206-213 207 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.2.206-213.2234 Figure 1. Drug molecules with benzothiazole skeleton. Scheme 1. Preparation of 1:1 co-crystal of 4-fluorobenzoic and 2-aminobenzothiazol. 1H and 13C NMR spectra were obtained at 500 MHz Jeol (JNM ECX-500) NMR machines with CDCl3 as the solvent. Mass spectra (TOF-MS ES+) were measured on a Bruker Impact HD QTOF Micro mass spectrometer. Melting points were recorded on a Digital Melting Point Apparatus (Model No. MT-934) and are uncorrected. TLC was performed on silica gel 60F254 (Merck) plates. Single crystal data was collected on Agilent Technologies (Oxford Diffraction) Supernova single crystal diffractometer. 2.2. Preparation of co-crystal 1:1 Co-crystals of 4-fluorobenzoic acid and 2-amino benzothiazol (III, 0.270 g; 0.93 mmol) were obtained from the equimolar mixture of 4-fluorobenzoic acid (I, 0.280 g, 2 mmol) and 2-aminobenzothiazol (II, 0.301 g, 2 mmol) in aqueous ethanol (1:1, v:v). Slow evaporation of the solution at room temperature resulted in the formation of white block-shaped co-crystals (Scheme 1). 4-Fluorobenzoic acid (I): Color: White powder. FT-IR (KBr, ν, cm-1): 3082, 2987, 2826, 2667, 2552, 1674, 1599, 1509, 1423, 1293, 1224, 1130, 924, 847, 765. 1H NMR (500 MHz, CDCl3, δ, ppm): 9.97 (1H, s, OH), 8.14-8.12 (2H, m, Ar-H), 7.15 (2H, t, J = 8.50 Hz, Ar-H). 2-Aminobenzothiazol (II): Color: White powder. FT-IR (KBr, ν, cm-1): 3060, 1716, 1588, 1503, 1420, 1276, 1014, 829. 1H NMR (500 MHz, CDCl3, δ, ppm): 7.59 (1H, dd, J = 7.92, 1.30, 1.25 Hz, Ar-H), 7.54 (1H, dd, J = 8.05, 1.15 Hz, Ar-H), 7.31 (1H, td, J = 7.33, 1.30, 1.25 Hz, Ar-H), 7.13 (1H, td, J = 7.58, 7.68, 1.20 Hz, Ar-H), 5.45 (2H, s, NH2). Co-crystal of 2-aminobenzothiazol and 4-fluorobenzoic acid (1:1) (III): Color: Colorless crystal. FT-IR (KBr, ν, cm-1): 3401, 3305, 3169, 2358, 1671, 1624, 1600, 1542, 1509, 1453, 1329, 1228 1126, 1091, 854, 744. 1H NMR (500 MHz, CDCl3, δ, ppm): 8.15 (2H, dd, J = 8.90, 5.5 Hz, Ar-H), 7.58-7.54 (2H, m, Ar-H), 7.34 (1H, t, J = 7.55 Hz, Ar-H), 7.17-7.12 (3H, m, Ar-H), 6.73 (2H, s, NH2). 13C NMR (125 MHz, CDCl3, δ, ppm): 170.33, 168.08, 166.84, 164.83, 149.42, 132.51, 132.44, 129.31, 127.07, 126.35, 122.62, 121.06, 118.01, 115.53, 115.35. 2.3. Crystal structure determination and refinement Single block crystals of the compounds, C14H11N2O2S (III) with dimensions of 0.30 × 0.20 × 0.20 mm were used for data collection. X-ray diffraction study was done on Agilent Technologies (Oxford Diffraction) Supernova single crystal diffractometer using radiation (λ = 1.54184 Å). X-ray intensity data of 3568 reflections were collected at 293(2) K and out of these reflections 2280 were found unique. The intensities were measured by ω scan mode for θ ranges 3.75 to 67.10°, where 2158 reflections with I > 2σ (I) were treated as observed. Data was corrected for Lorentz-polarization and absorption factors. The molecular structure was solved by direct methods using SHELXT package [41]. Multisolution tangent refinement was used. All non-hydrogen atoms of the molecule were located in the best E-map and refined in anisotropic approximation using SHELXS [41]. All hydrogen atoms were geometrically fixed and allowed to ride on the corresponding non-H atoms with N-H= 0.86 Å, C-H= 0.93-0.98 Å and Uiso(H)=1.5 Ueq of the attached C atoms for methyl groups and 1.2 Ueq(N, C) for other H atoms. The geometry of the molecule was calculated using the WinGX [42], PARST [43], and PLATON [44] software. The crystallo- graphic data are summarized in Table 1. 2.4. Hirshfeld surfaces calculations In order to carry out the Hirshfeld surface analysis and to create fingerprint plots, Crystal Explorer 17.5 program [45] was used, for which the crystallographic information file (CIF) was used as input. The molecular Hirshfeld surface of compound III was generated using a standard (high) surface resolution with the 3D dnorm surfaces, the shape index and curvature. The surfaces were shown to be transparent to allow visualization of the molecular moiety in a similar orientation for all of the structures around which they were calculated. 2D fingerprint graphs are plotted by accumulating (di, de) pairs. 3. Results and discussion 3.1. Synthesis We have compared the 1H NMR data of compounds I, II, and III (Figure 2). In the 1H NMR spectrum of compound II, peak for -NH2 appeared at δH 5.45 ppm (2H, s), in this case, a sharp singlet peak was obtained. Whereas a small broad singlet peak was recorded at δH 6.73 ppm (2H, brs) for the same -NH2 protons in co-crystal III. This little bit higher value indicates there must be some deficiency of electron density over -NH2 in the co-crystal III, which is definitely due to the formation of strong hydrogen bonds. Other peaks are almost comparable in the individual as well as co-crystal form. 3.2. Single crystal X-ray structure analysis An ORTEP view [46] of the co-crystal III with atomic labeling is shown in Figure 3. The bond lengths and angles in the compounds are comparable with literature values [47] and the selected bond distances and angles are shown in Table 2. 208 Banerjee et al. / European Journal of Chemistry 13 (2) (2022) 206-213 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.2.206-213.2234 Table 1. Crystal data and structure refinement for compound III. Empirical formula C14H11FN2O2S Formula weight 290.31 Temperature (K) 293(2) Crystal system Monoclinic Space group P21/c a, (Å) 11.7869(14) b, (Å) 4.0326(5) c, (Å) 27.625(3) α (°) 90 β (°) 92.731(10) γ (°) 90 Volume (Å3) 1311.6(3) Z 4 ρcalc(g/cm3) 1.470 μ (mm-1) 2.345 F(000) 600.0 Crystal size (mm3) 0.3 × 0.2 × 0.2 Radiation CuKα (λ = 1.54184) 2Θ range for data collection (°) 7.508 to 134.202 Index ranges -13 ≤ h ≤ 14, -3 ≤ k ≤ 4, -28 ≤ l ≤ 32 Reflections collected 3568 Independent reflections 2280 [Rint = 0.0262, Rsigma = 0.0413] Data/restraints/parameters 2280/0/189 Goodness-of-fit on F2 1.009 Final R indexes [I≥2σ (I)] R1 = 0.0446, wR2 = 0.1139 Final R indexes [all data] R1 = 0.0615, wR2 = 0.1274 Largest diff. peak/hole (e.Å-3) 0.22/-0.28 Figure 2. Comparison of 1H NMR of compounds I, II and co-crystal III. Banerjee et al. / European Journal of Chemistry 13 (2) (2022) 206-213 209 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.2.206-213.2234 Table 2. Selected bond lengths and angles for compound III. Atom Atom Length (Å) Atom Atom Length (Å) S3 C4 1.741(3) C31 C32 1.383(4) S3 C2 1.755(3) C35 C34 1.367(4) F37 C34 1.354(3) C35 C36 1.376(4) O40 C38 1.292(3) C34 C33 1.373(4) C4 C9 1.404(4) N1 C9 1.385(3) C4 C5 1.377(4) C8 C9 1.389(4) O39 C38 1.219(3) C8 C7 1.374(4) C2 N10 1.317(4) C7 C6 1.391(5) C2 N1 1.315(3) C32 C33 1.378(4) C31 C36 1.389(4) C6 C5 1.378(4) C31 C38 1.495(4) Atom Atom Atom Angle (°) Atom Atom Atom Angle (°) C4 S3 C2 89.29(12) C2 N1 C9 111.0(2) C9 C4 S3 109.27(19) C35 C36 C31 120.9(3) C5 C4 S3 128.7(2) O40 C38 C31 115.4(2) C5 C4 C9 122.0(3) O39 C38 O40 124.0(3) N10 C2 S3 120.9(2) O39 C38 C31 120.6(2) N1 C2 S3 115.12(19) C7 C8 C9 119.1(3) N1 C2 N10 124.0(3) N1 C9 C4 115.3(2) C36 C31 C38 121.9(2) N1 C9 C8 125.7(2) C32 C31 C36 119.1(3) C8 C9 C4 119.0(2) C32 C31 C38 119.0(2) C8 C7 C6 121.1(3) C34 C35 C36 118.2(3) C33 C32 C31 120.7(3) F37 C34 C35 119.0(3) C5 C6 C7 120.9(3) F37 C34 C33 118.2(3) C4 C5 C6 117.9(3) C35 C34 C33 122.8(3) C34 C33 C32 118.3(3) Figure 3. The structure of the co-crystal (III), displacement ellipsoids are drawn at 50% probability level. The X-ray diffraction analyses showed that asymmetric unit of co-crystal of compound III consisted of two crystallo- graphically independent molecules one of 2-aminobenzothiazol IIIA and other of 4-fluorobenzoic IIIB. The geometrical para- meters of 2-aminobenzothiazol moiety shows slightly different and are in good agreement with those of related co-crystal structure (C14H10BrN3O4S) [48]. The double bond character of the N1-C2 is confirmed by its distance of 1.315(3) Å (IIIA). The S3-C4 = 1.741(3) Å, S3-C2 = 1.755(3) Å (IIIA) exhibit small variations from the reported for values of 1.764 Å, 1.741 Å for related co-crystal (C14H10BrN3O4S) [48], these differences may be due to ring strain and electron delocalization. In addition, the bond distance of 1.317(4) Å for C2-N10 shows variation from its reported value of 1.342 Å in similar co-crystal (C14H10BrN3O4S) [48]. The bond angles C9- N1-C2 = 111.0(2)°, N1-C2-S3 = 115.12(19)° and C2-S3-C4 = 89.29(12)° of 2-aminobenzothiazol moiety (IIIA) is found to be comparable [110.26°, 115.97°, 88.69°] with the value of the reported co-crystal (C14H10BrN3O4S) [48]. In 4-fluorobenzoic acid moiety (IIIB), the bond distance the double bond C38-O39 = 1.219(3) Å and single bond C38-O40= 1.292(3) Å shows variation from [1.251 Å, 1.282 Å] with the reported co-crystal (C7H5O2F) [49]. In the benzene rings systems, the endocyclic angles at C5, C33, C34 and C35 are narrowed while those at C4 and C7 are expanded from 120°, respectively. The substituted group makes torsion angles N10-C2-N1-C9 = -179.4(3)° (IIIA), C38-C31-C32-C33 = -179.2(3)° (IIIB) with the respective moieties. All rings of compound III are planer in conformation with maximum deviation for C1 [0.024(3)] of 2- aminobenzothiazol ring, and for C32 [0.007(3)] of benzene ring. The dihedral angle between aminobenzothiazol and fluoro- benzoic acid moieties of 170.78(8)° shows that both the moieties are to equatorial to each other. Hydrogen bonding is one of the most important non- covalent interactions that can determine and control the assembly of molecules and ions. Analysis of the crystal packing showed only intermolecular hydrogen bonds in compound III. Both the active H atoms of the NH2 group participate in inter- molecular N-H···O type hydrogen bonds in compound III. In this co-crystal structure, the molecules are linked by a pair of N10- H102···O39 and O40-H401···N1 hydrogen bonds with inversion dimmers forming R42(8) and R44(16) ring motifs [50] (Figure 4). These dimmers are further connected by another hydrogen bond N10-H101···O39 in a two-dimensional network, thus forming layer shaped structures along b-axis (Figure 5). The best packing view for compounds III is obtained along b-axis. Details about all interactions are given in Table 3. 3.3. Hirshfeld surface analysis For obtaining additional insight into the intermolecular interaction of molecular crystals, the Hirshfeld surface is a suitable tool for qualitative and quantitative study and mapping of intermolecular close contacts in molecular crystals. Figure 6 shows the 3D Hirshfeld dnorm surfaces, the shape index and curvature for co-crystal III, which are achieved by mapping dnorm over the Hirshfeld surface in the range from -0.4870 to 1.3305 a.u. for co-crystal III. This indicates interactions between neighboring molecules [51,52]. 210 Banerjee et al. / European Journal of Chemistry 13 (2) (2022) 206-213 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.2.206-213.2234 Table 3. Geometry of inter- and intramolecular interactions for compound III. D–H···A D–H, Å H···A, Å D···A, Å θ(D–H···A), deg N10-H101···O39 i 0.84(4) 2.13(4) 2.883(4) 151(3) N10-H102···O39 ii 0.78(4) 2.05(4) 2.830(4) 176(4) O40-H401···N1 0.82 1.85 2.664(3) 171 Symmetry codes: (i) x, 1+y, z; (ii) 1-x, 1-y, -z. Figure 4. A plot of molecules of the co-crystal III showing the formation of dimmers by intermolecular N-H···O and O-H···N hydrogen bonds forming 𝑅𝑅42(8) and 𝑅𝑅44(16) ring motif. Figure 5. Packing view of molecules viewed down the b-axis within the unit cell of compound III. (a) (b) (c) Figure 6. Hirshfeld surface: (a) dnorm, (b) shape index, and (c) curvature for co-crystal III. In Figure 6a, we see that the long cyclic hydrogen bond between H102 and O39 is associated with two large red spots of the same size, as identical pair on the surface forming inversion dimers. Figure 6b shows the lack of self-comple- mentary patches of triangles on the shape index surface, which symbolizes a weaker and longer C-H···π stacking. Figure 6c displays very small regions of green (relatively flat) separated by dark blue boundaries (large positive curvature), indicating the involvement of any aromatic-aromatic sequence in co- crystal III. The corresponding 2-D fingerprint plots for Hirshfeld surfaces of compound III displaying major intermolecular interactions with their percentage of contribution to the total Hirshfeld surface area are shown in Figure 7 along with labeled intermolecular contact values [53]. Table 4 shows that H···H interaction following H···C/C···H interaction with 34.1 and 13.5%, respectively, had a significant contribution among all total Hirshfeld surfaces. The O···H/H···O intermolecular interactions clearly appear as distinct spikes in the 2D fingerprint. Banerjee et al. / European Journal of Chemistry 13 (2) (2022) 206-213 211 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.2.206-213.2234 Table 4. Summary of the various intermolecular contacts contributed to the Hirshfeld surface for co-crystal III. Intermolecular interaction Contribution (%), >1.0 H···H 34.1 H···C/C···H 13.5 F···H/H···F 11.3 O···H/H···O 10.8 C···C 9.0 H···N/N···H 3.1 F···C/C···F 2.9 S···C/C···S 2.1 O···C/C···O 1.7 C…N/N…C 1.1 Figure 7. 2D fingerprint plots of co-crystal III. (a) (b) (c) Figure 8. Energy framework diagram for (a) electrostatic, (b) dispersion and (c) total interaction energy. 212 Banerjee et al. / European Journal of Chemistry 13 (2) (2022) 206-213 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.2.206-213.2234 The energy framework calculations is estimated from a single-point molecular wavefunction at B3LYP/6-31G(d,p) basis set [54,55]. The interaction energies viz., electrostatic, polarization, dispersion, and repulsion, between the molecular pairs were calculated. The visualization of different interaction energies; Coulomb interaction energy (red), dispersion energy (green), and total interaction energy (blue) of the compound are shown in Figure 8. The cylinders in the energy framework represent the relative strengths of molecular packing in different directions. The molecular pair-wise interaction energies calculated for the construction of energy frameworks are used to evaluate the net interaction energies. The total interaction energies for electrostatic, polarization, dispersion and repulsion are -124.8, -29.1, -16.5, and 147.8 kJ/mol, respectively. The total energy is -76.5 kJ/mol. 4. Conclusions A supramolecular compound with different topologies has been prepared and structurally characterized. Single crystal X- ray diffraction studies led to unambiguous structure determi- nation. The different hydrogen bond interaction modes led to stabilization and formation of co-crystals. Hydrogen bonds are viewed as the strongest and most directional of the inter- molecular interactions which play an incomparable role in the formation of supramolecular structure. The dihedral angle between aminobenzothiazol and fluorobenzoic acid moieties is 170.78(8)°. Hirshfeld surface analysis was done to quantify and identify the robust synthons and to understand the overall packing pattern of the co-crystal. Acknowledgements Vivek Kumar Gupta is thankful to University of Jammu, Jammu, India, for financial support under Rashtriya Uchchatar Shiksha Abhiyan (RUSA) 2.0 Project. (Ref. No: RUSA/JU/2/2019-20/111/3588-3636). Bubun Banerjee is grateful to Akal University for financial assistance. Supporting information CCDC-1983312 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/, or by e-mailing data_request@ ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(0)1223-336033. Disclosure statement Conflict of interest: The authors declare that they have no conflict of interest. Ethical approval: All ethical guidelines have been adhered. Sample availability: Samples of the compounds are available from the author. CRediT authorship contribution statement Conceptualization: Vivek Kumar Gupta, Bubun Banerjee; Methodology: Bubun Banerjee, Varun Sharma; Software: Varun Sharma, Aditi Sharma; Validation: Vivek Kumar Gupta, Bubun Banerjee; Formal Analysis: Gurpreet Kaur, Varun Sharma; Investigation: Bubun Banerjee, Varun Sharma; Resources: Vivek Kumar Gupta, Bubun Banerjee; Data Curation: Varun Sharma, Aditi Sharma, Gurpreet Kaur; Writing - Original Draft: Bubun Banerjee, Varun Sharma; Writing - Review and Editing: Bubun Banerjee, Vivek Kumar Gupta; Visualization: Bubun Banerjee, Vivek Kumar Gupta; Funding acquisition: Vivek Kumar Gupta, Bubun Banerjee; Supervision: Vivek Kumar Gupta, Bubun Banerjee; Project Administration: Vivek Kumar Gupta, Bubun Banerjee. ORCID and Email Bubun Banerjee banerjeebubun@gmail.com https://orcid.org/0000-0001-7119-9377 Varun Sharma varunsharma5228@gmail.com https://orcid.org/0000-0003-2866-8638 Aditi Sharma aditi2195sharma@gmail.com https://orcid.org/0000-0001-7777-0896 Gurpreet Kaur kaur80328@gmail.com https://orcid.org/0000-0002-9685-7927 Vivek Kumar Gupta vivek.gupta2k9@gmail.com https://orcid.org/0000-0003-2471-5943 References [1]. Hong, Y.-L.; Manjunatha Reddy, G. N.; Nishiyama, Y. Selective detection of active pharmaceutical ingredients in tablet formulations using solid-state NMR spectroscopy. Solid State Nucl. Magn. Reson. 2020, 106, 101651. [2]. Curatolo, W. Physical chemical properties of oral drug candidates in the discovery and exploratory development settings. Pharm. Sci. Technolo. Today 1998, 1, 387–393. [3]. Childs, S. L.; Chyall, L. J.; Dunlap, J. T.; Smolenskaya, V. N.; Stahly, B. C.; Stahly, G. P. Crystal engineering approach to forming cocrystals of amine hydrochlorides with organic acids. 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Copyright © 2022 by Authors. This work is published and licensed by Atlanta Publishing House LLC, Atlanta, GA, USA. The full terms of this license are available at http://www.eurjchem.com/index.php/eurjchem/pages/view/terms and incorporate the Creative Commons Attribution-Non Commercial (CC BY NC) (International, v4.0) License (http://creativecommons.org/licenses/by-nc/4.0). By accessing the work, you hereby accept the Terms. This is an open access article distributed under the terms and conditions of the CC BY NC License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited without any further permission from Atlanta Publishing House LLC (European Journal of Chemistry). No use, distribution or reproduction is permitted which does not comply with these terms. Permissions for commercial use of this work beyond the scope of the License (http://www.eurjchem.com/index.php/eurjchem/pages/view/terms) are administered by Atlanta Publishing House LLC (European Journal of Chemistry). http://www.eurjchem.com/index.php/eurjchem/pages/view/terms http://creativecommons.org/licenses/by-nc/4.0 http://www.eurjchem.com/index.php/eurjchem/pages/view/terms 1. Introduction 2. Experimental 2.1. General 2.2. Preparation of co-crystal 2.3. Crystal structure determination and refinement 2.4. Hirshfeld surfaces calculations 3. Results and discussion 3.1. Synthesis 3.2. Single crystal X-ray structure analysis 3.3. Hirshfeld surface analysis 4. Conclusions Acknowledgements Supporting information Disclosure statement CRediT authorship contribution statement ORCID and Email References PrintField10: PrintField11: PrintField12: PrintField13: PrintField14: PrintField15: PrintField16: PrintField17: PrintField20: PrintField21: PrintField22: PrintField23: PrintField24: PrintField25: PrintField26: PrintField27: