Ibuprofen, a household pharmaceutical belonging to the racemic mimic class-chirality, diastereochemical details, packing and overlay of the pair within the (S)(+) crystals European Journal of Chemistry 16 (3) (2025) 327-330 European Journal of Chemistry ISSN 2153-2249 (Print) / ISSN 2153-2257 (Online) – Copyright © 2025 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.16.3.327-330.2679 European Journal of Chemistry View Journal Online View Article Online Ibuprofen, a household pharmaceutical belonging to the racemic mimic class-chirality, diastereochemical details, packing and overlay of the pair within the (S)(+) crystals Ivan Bernal 1,2 and Roger Lalancette 1,* 1 Carl A. Olson Memorial Laboratories, Department of Chemistry, Rutgers University, 73 Warren St., Newark, NJ, 07102 USA 2 Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Private Bag 3, 2050 Johannesburg, South Africa * Corresponding author at: Carl A. Olson Memorial Laboratories, Department of Chemistry, Rutgers University, 73 Warren St., Newark, NJ, 07102 USA. e-mail: roger.lalancette@gmail.com (R. Lalancette). 10.5155/eurjchem.16.3.327-330.2679 Received: 2 March 2025 Received in revised form: 20 June 2025 Accepted: 26 July 2025 Published online: 30 September 2025 Printed: 30 September 2025 We have discovered that enantiopure and racemic Ibuprofen crystallize with nearly the same cell constants, the former in space group P21, the latter in P21/c. As expected from a pair that belongs to the racemic mimic class, the values of Z’ are 2.0 and 1.0, respectively. Interestingly, despite the fact that one is enantiopure and the other is a racemate, they form the classical dicarboxylate dimer one is familiar with in elemental chemistry and with nearly identical geometrical parameters, the enantiopure sitting at a true lattice inversion center, and the other one at a pseudo-inversion point located at 0.5000, 0.4458, and 0.5000. Packing diagrams are provided that show the remarkable degree to which they agree. Overlay diagrams generated with Mercury illustrate the extent to which the pair of enantiopure species resemble each other; the differences being largely small diastereoisomeric discrepancies and without a doubt the result of anisotropy in packing forces. Finally, within accepted limits for π-π bondings, there are no significant interactions between the phenyl rings in either crystalline form. Ibuprofen Chiral drugs Racemic mimics Racemic crystals Diastereoisomerism Sohncke space groups Cite this: Eur. J. Chem. 2025, 16(3), 327-330 Journal website: www.eurjchem.com 1. Introduction In the past, we have described our interest in the mode of crystallization described as racemic mimic [1-3] that seems to have been ignored, or gone unnoticed for a long time even though our searches in CCDC [4] suggest that it occurs over the entire spectrum of chemical compounds in that database. So, to begin this report, we state that the most fundamental characteristics of crystalline materials belonging in that class are: (a) racemic materials and their mimic crystals have nearly identical cell constants; (b) racemate crystals contain pairs of molecules related by operations of the second kind; e.g., mirrors, inversions, and roto-inversions; (c) racemic mimic crystals contain the same number of molecules in the unit cell as those in (b); but they support only symmetry operations of the first kind; e.g., translation, rotations, etc. Because we have already given the necessary historical recount of how, where, and by whom this was done, we direct the interested reader to those earlier sources [1-3]. The example selected in this case is the widely used drug Ibuprofen [5,6]. 2. Experimental The properties of all substances described here were obtained from the originals provided by the CCDC [4] where we carried out our search. (S)-(+)-Ibuprofen; Dexibuprofen; DrugBank: DB09213; PDB chemical component code: IBP, appearing as JEKNOC12 [5] and racemic Ibuprofen; Advil; Motrin; Nurofen; DrugBank: DB01050, appearing as IBPRAC01 [6] are the two species studied here as illustrations of a purely organic racemic mimic pair of drugs. The chiral center assignments and molecular overlay information were obtained with MERCURY [7]. The final figures were drawn with DIAMOND [8]. 3. Results and discussion In Figure 1, we display a picture of the labeled molecule present in the racemic form-space group P21/c (note: see below for a comparison of the cell constants of the crystals that have been compared in this publication). The packing characteristics of this species are interesting, as shown in Figure 2. ABSTRACT RESEARCH ARTICLE KEYWORDS https://dx.doi.org/10.5155/eurjchem.16.3.327-330.2679 https://www.eurjchem.com/ https://dx.doi.org/10.5155/eurjchem.16.3.327-330.2679 mailto:roger.lalancette@gmail.com http://www.eurjchem.com/ https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.16.3.327-330.2679&domain=pdf&date_stamp=2025-09-30 328 Bernal and Lalancette / European Journal of Chemistry 16 (3) (2025) 327-330 2025 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.16.3.327-330.2679 Figure 1. C2 is the chiral center. Note the precision with which the hydrogens of the terminal methyl fragments were located. Figure 2. A view of the unit cell projected down the b-axis. Figure 3. Two molecules of the racemic form of ibuprofen showing the hydrogen-bonded pairs that link the infinite strings. Figure 4. A b projection showing how the molecules stack in a view suggesting π-π bonding; however, the ring centroid distances are those of the a-unit cell, indicating the stacking expected from packing forces. The molecules pack in pairs, related by inversion centers, in an interesting tail-to-tail fashion, readily shown on the top left and bottom right, forming infinite rows of such pairs. In turn, adjacent members of such rows form hydrogen bonds in the classical acetic acid dimer mode, Figure 3. Now, we proceed to examine the case of the optically active form, using Figure 4 to illustrate the packing of the molecules in a unit cell. Let us now investigate the effect of losing the inversion centers- see Figure 5. Here we note that, although crystallographic inversion centers have been lost in space group P21, pseudo-inversion centers persist, and the center-of- mass of the entire pattern is located approximately at 0.5000, 0.4458, 0.5000; however, recalling that in P21, the origin in y is arbitrary and must be fixed, we can place the center of mass at exactly ½, ½, ½ (or ½,0, ½). As for the inversion centers at the hydrogen-bonded dimers present in the racemate, those in the (S)-enantiomer, they appear atop Figure 5 and are slightly asymmetric, as imperfect centers should be. The O···H distances are 1.648 and 1.776 Å. If the members of the pairs in the chiral sample are different, one can ask the following. How different is this? This question is answered with Figure 6 generated using MERCURY [4] and DIAMOND [5], as mentioned above. Bernal and Lalancette / European Journal of Chemistry 16 (3) (2025) 327-330 329 2025 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.16.3.327-330.2679 Table 1. Comparison of cell dimensions. CSD name a (Å) b (Å) c (Å) β (°) Volume (ų) Space group Z Z’ R T (K) IBPRAC01 [3] 14.397(8) 7.818(4) 10.506(6) 99.70(3) 1165.605 P2₁/c 4.0 1.0 5.30 100 JEKNOC12 [2] 12.109(1) 7.960(<1) 13.362(1) 111.95(<1) 1194.514 P2₁ 4.0 2.0 3.80 99 Figure 5. Depicted are areas where one can investigate the inversion-centered hydrogen-bonded and methyl-methyl pairs observed above in Figure 2. C11 and C13 methyl group pairs are drawn in blue for the reader’s convenience; hydrogen-bonded pairs are joined by dotted lines for the same purpose. Figure 6. Using MERCURY [4], Molecule 2 was overlayed on Molecule 1 using only the command Flexibility-note that the chiral centers perfectly overlay (even the hydrogens), although refined separately. Finally, since the fundamental characteristics of a racemic mimic pair are; (a) the pair crystallizes as a racemate and in a Sohncke space group, which is a proper subgroup of the former. This is so in this case. (b) the cell constants are nearly identical in both cases; this is also the case here, as shown in Table 1. 4. Conclusions The long- and widely-used drug Ibuprofen has been found to crystallize in the Racemic Mimic category. Whether or not that is reflected in its biological properties, good or bad, needs to be determined in a suitable environment. We hope that, having provided that clue to the pharmaceutical laboratories, they will decide to proceed accordingly. Hopefully, this idea may have some generality and is found to be valid in additional biologically active compounds currently in use. Disclosure statement Conflict of interest: The authors declare that they have no conflict of interest. Ethical approval: All ethical guidelines have been adhered. CRediT authorship contribution statement Conceptualization: Ivan Bernal and Roger Lalancette; Methodology: Ivan Bernal and Roger Lalancette; Validation: Ivan Bernal and Roger Lalancette; Formal Analysis: Ivan Bernal and Roger Lalancette; Investigation: Ivan Bernal and Roger Lalancette; Resources: Ivan Bernal and Roger Lalancette; Data Curation: Ivan Bernal and Roger Lalancette; Writing - Original Draft: Ivan Bernal and Roger Lalancette; Writing - Review and Editing: Ivan Bernal and Roger Lalancette; Visualization: Ivan Bernal and Roger Lalancette; Funding acquisition: Ivan Bernal and Roger Lalancette; Supervision: Ivan Bernal and Roger Lalancette; Project Administration: Ivan Bernal and Roger Lalancette. ORCID and Email Ivan Bernal bernalibg@gmail.com https://orcid.org/0000-0002-8168-5907 Roger Lalancette roger.lalancette@gmail.com rogerlal@newark.rutgers.edu https://orcid.org/0000-0002-3470-532X References [1]. Wood, M. R.; Mikhael, S.; Bernal, I.; Lalancette, R. A. Erdmann’s Anion—an Inexpensive and Useful Species for the Crystallization of Illicit Drugs after Street Confiscations. Chemistry (Basel) 2021, 3 (2), 598–611. [2]. Bernal, I.; Lalancette, R. A. Racemic Mimics. Part 1. Nickel Coordination Compounds. Acta Crystallogr. C Struct. Chem. 2025, 81 (Pt 4), 181–187. [3]. Levendis, D. C.; Bernal, I. The Grubbs Catalyst – Dichlorido(1-(2,6- Diethylphenyl)-3,5,5-Trimethyl-3-Phenylpyrrolidin-2-Ylidene)-(5- nitro-2-[(propan-2-yl)oxy]phenylMethylidene)Ruthenium(II) – Some Observations on the Crystallography and Stereochemistry of a Racemic Mimic Pair. Z. Kristallogr. Cryst. Mater. 2025, 240 (5–6), 173– 179. [4]. Groom, C. R.; Bruno, I. J.; Lightfoot, M. P.; Ward, S. C. The Cambridge Structural Database. Acta Crystallogr. B Struct. Sci. Cryst. Eng. Mater. 2016, 72 (Pt 2), 171–179. mailto:bernalibg@gmail.com https://orcid.org/0000-0002-8168-5907 mailto:roger.lalancette@gmail.com mailto:rogerlal@newark.rutgers.edu https://orcid.org/0000-0002-3470-532X 330 Bernal and Lalancette / European Journal of Chemistry 16 (3) (2025) 327-330 2025 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.16.3.327-330.2679 [5]. King, M. D.; Buchanan, W. D.; Korter, T. M. Understanding the Terahertz Spectra of Crystalline Pharmaceuticals: Terahertz Spectroscopy and Solid-State Density Functional Theory Study of (S)- (+)-Ibuprofen and (RS)-Ibuprofen. J. Pharm. Sci. 2011, 100 (3), 1116– 1129. [6]. Shankland, N.; Florence, A. J.; Cox, P. J.; Sheen, D. B.; Love, S. W.; Stewart, N. S.; Wilson, C. C. Crystal Morphology of Ibuprofen Predicted from Single-Crystal Pulsed Neutron Diffraction Data. Chem. Commun. (Camb.) 1996, No. 7, 855–856. [7]. Macrae, C. F.; Sovago, I.; Cottrell, S. J.; Galek, P. T. 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Permissions for commercial use of this work beyond the scope of the License (https://www.eurjchem.com/index.php/eurjchem/terms) are administered by Atlanta Publishing House LLC (European Journal of Chemistry). https://www.eurjchem.com/index.php/eurjchem/terms http://creativecommons.org/licenses/by-nc/4.0 https://www.eurjchem.com/index.php/eurjchem/terms 1. Introduction 2. Experimental 3. Results and discussion 4. Conclusions Disclosure statement CRediT authorship contribution statement ORCID and Email References PrintField10: PrintField11: PrintField12: PrintField13: PrintField20: PrintField21: PrintField22: PrintField23: