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Fundamental theoretical and practical investigations of the polymorph formation of small amphiphilic molecules, their co-crystals and salts

  • Thomas Martin , Paul Niemietz , Dominik Greim , Philipp Ectors , Jürgen Senker EMAIL logo , Dirk Zahn EMAIL logo and Josef Breu EMAIL logo
Published/Copyright: August 17, 2016
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Zeitschrift für Kristallographie - Crystalline Materials
From the journal Zeitschrift für Kristallographie - Crystalline Materials Volume 232 Issue 1-3

Abstract

The amphiphilic nature of benzoic acid, benzoates and benzamide causes an unexpected rich polymorphism. Featuring rather rigid and small molecular structures these compounds are ideal model systems for gaining a more fundamental understanding of molecular polymorphism by systematic and concerted investigations. The hydrophilic head allows for hydrogen bonding while the phenyl moiety gives rise to various π-stacking modes. Variations of hydrogen bonding versus π-stacking modes give rise to four polymorphs of benzamide. The central synthon in all phases is a dimer where hydrophilic units form double hydrogen bonds. As suggested by MD simulations of the nucleation process, variations of the crystallization conditions trigger whether the first self-assembly occurs via the hydrophilic head or the hydrophophic tail groups. Based on NMR crystallographic investigations for the co-crystallization of benzamide with benzoic acid, we observed yet another variation of the balance of the two dominating intermolecular interactions leading to the formation of a 1:1 co-crystal. The average crystal structure resembles the packing motive of pure benzoic acid with alternating ribbons of homogenous benzamide and benzoic acid dimers. For alkali-benzoate salts a coordination dilemma arises that is of general importance for many active pharmaceutical ingredients (APIs). A 1:1 stoichiometry requires condensation of coordination polyhedra of small inorganic cations which in turn causes steric stress that varies with the relative volumes of cation and anion. Interestingly, one way of resolving the dilemma is microphase separation which is directly related to the amphiphilic character of benzoate.

Keywords: amphiphilic molecules; benzamide; benzoate; benzoic acid; co-crystal; crystal structure; polymorphism

Acknowledgments

This work was financially supported by the Deutsche Forschungsgemeinschaft (SPP1415).

References

[1] J. Bernstein, Polymorphism of dyes and pigments, in Polymorph. Mol. Cryst., Oxford University Press, Oxford, p. 257, 2007.10.1093/acprof:oso/9780199236565.001.0001Search in Google Scholar

[2] K. Kadish, R. Guilard, K. M. Smith, The Porphyrin Handbook: Applications of Phthalocyanines, Elsevier Science, 2012.Search in Google Scholar

[3] J. M. Oyarzún, Pigment Processing: Physico-Chemical Principles, Vincentz Network GmbH & Co KG, 2000.Search in Google Scholar

[4] B. Olenik, G. Thielking, Polymorphism and the organic solid state: influence on the Optimization of Agrochemicals, in Mod. Methods Crop Prot. Res., Wiley-VCH, p. 249, 2012.10.1002/9783527655908.ch10Search in Google Scholar

[5] R. J. Davey, N. Blagden, G. D. Potts, R. Docherty, Polymorphism in molecular crystals: Stabilization of a metastable form by conformational mimicry. J. Am. Chem. Soc.1997, 119, 1767.10.1021/ja9626345Search in Google Scholar

[6] S. R. Hall, P. V. Kolinsky, R. Jones, S. Allen, P. Gordon, B. Bothwell, D. Bloor, P. A. Norman, M. Hursthouse, A. Karaulov, J. Baldwin, M. Goodyear, D. Bishop, Polymorphism and nonlinear optical activity in organic crystals. J. Cryst. Growth1986, 79, 745.10.1016/0022-0248(86)90549-XSearch in Google Scholar

[7] W. Wang, M. Aggarwal, J. Choi, T. Gebre, A. D. Shields, B. G. Penn, D. O. Frazier, Solvent effects and polymorphic transformation of organic nonlinear optical crystal L-pyroglutamic acid in solution growth processes. J. Cryst. Growth1999, 198–199, 578.10.1016/S0022-0248(98)01041-0Search in Google Scholar

[8] J. Haleblian, W. McCrone, Pharmaceutical applications of polymorphism. J. Pharm. Sci.1969, 58, 911.10.1002/jps.2600580802Search in Google Scholar PubMed

[9] R. Hilfiker, Polymorphism: In the Pharmaceutical Industry, John Wiley & Sons, 2006.10.1002/3527607889Search in Google Scholar

[10] J. Bernstein, Polymorphism in Molecular Crystals, Oxford University Press, Oxford, 2007.10.1093/acprof:oso/9780199236565.001.0001Search in Google Scholar

[11] J. D. Dunitz, J. Bernstein, Disappearing polymorphs. Acc. Chem. Res.1995, 28, 193.10.1021/ar00052a005Search in Google Scholar

[12] D.-K. Bučar, R. W. Lancaster, J. Bernstein, Disappearing polymorphs revisited. Angew. Chem. Int. Ed.2015, 54, 6972.10.1002/anie.201410356Search in Google Scholar PubMed PubMed Central

[13] E. Gibney, Software predicts slew of fiendish crystal structures. Nature2015, 527, 20.10.1038/527020aSearch in Google Scholar PubMed

[14] W. Ostwald, Studien über die Bildung und Umwandlung fester Körper. 1. Abhandlung: Übersättigung und Überkaltung. Z. Phys. Chem.1897, 22, 289.10.1515/zpch-1897-2233Search in Google Scholar

[15] U. Kolb, T. Gorelik, C. Kübel, M. T. Otten, D. Hubert, Towards automated diffraction tomography: part I – Data acquisition. Ultramicroscopy2007, 107, 507.10.1016/j.ultramic.2006.10.007Search in Google Scholar PubMed

[16] U. Kolb, T. Gorelik, M. T. Otten, Towards automated diffraction tomography. Part II – Cell parameter determination. Ultramicroscopy2008, 108, 763.10.1016/j.ultramic.2007.12.002Search in Google Scholar PubMed

[17] L. Seyfarth, J. Seyfarth, B. V. Lotsch, W. Schnick, J. Senker, Tackling the stacking disorder of melon–structure elucidation in a semicrystalline material. Phys. Chem. Chem. Phys.2010, 12, 2227.10.1039/b919918gSearch in Google Scholar PubMed

[18] C. Martineau, J. Senker, F. Taulelle, NMR crystallography, annual reports on NMR spectroscopy. Annu. Reports NMR Spectrosc.2014, 82, 1.10.1016/B978-0-12-800184-4.00001-1Search in Google Scholar

[19] M. Schmidt, C. S. Zehe, R. Siegel, J. U. Heigl, C. Steinlein, H.-W. Schmidt, J. Senker, NMR-crystallographic study of two-dimensionally self-assembled cyclohexane-based low-molecular-mass organic compounds. CrystEngComm2013, 15, 8784.10.1039/c3ce41158cSearch in Google Scholar

[20] M. Schmidt, J. J. Wittmann, R. Kress, D. Schneider, S. Steuernagel, H.-W. Schmidt, J. Senker, Crystal structure of a highly efficient clarifying agent for isotactic polypropylene. Cryst. Growth Des.2012, 12, 2543.10.1021/cg300151sSearch in Google Scholar

[21] F. Wöhler, J. F. von Liebig, Untersuchungen über das Radikal der Benzoesäure. Ann. Der Pharm.1832, 3, 249.10.1002/jlac.18320030302Search in Google Scholar

[22] B. R. Penfold, J. C. B. White, The crystal and molecular structure of benzamide. Acta Crystallogr.1959, 12, 130.10.1107/S0365110X59000391Search in Google Scholar

[23] J. Thun, L. Seyfarth, J. Senker, R. E. Dinnebier, J. Breu, Polymorphism in benzamide: Solving a 175-year-old riddle. Angew. Chem. Int. Edit.2007, 46, 6729.10.1002/anie.200701383Search in Google Scholar PubMed

[24] P. Ectors, D. Ectors, D. Zahn, Structure and interactions in benzamide molecular crystals. Mol. Simul.2013, 39, 1079.10.1080/08927022.2013.794274Search in Google Scholar

[25] J. Thun, M. Schoeffel, J. Breu, Crystal structure prediction could have helped the experimentalists with polymorphism in benzamide. Mol. Simul.2008, 34, 1359.10.1080/08927020802208943Search in Google Scholar

[26] D. M. Benoit, P. Ectors, P. Duchstein, J. Breu, D. Zahn, A new polymorph (IV) of benzamide: structural characterization and mechanism of the I↔IV phase transition. Chem. Phys. Lett.2011, 514, 274.10.1016/j.cplett.2011.08.071Search in Google Scholar

[27] C. Butterhof, T. Martin, P. Ectors, D. Zahn, P. Niemietz, J. Senker, J. Breu, Thermoanalytical evidence of metastable molecular defects in form I of benzamide. Cryst. Growth Des.2012, 12, 5365.10.1021/cg3009706Search in Google Scholar

[28] P. Giannozzi, S. Baroni, N. Bonini, M. Calandra, R. Car, C. Cavazzoni, D. Ceresoli, G. L. Chiarotti, M. Cococ-cioni, I. Dabo, A. Dal Corso, S. de Gironcoli, S. Fabris, G. Fratesi, R. Gebauer, U. Gerstmann, C. Gougous-sis, A. Kokalj, M. Lazzeri, L. Martin-Samos, N. Marzari, F. Mauri, R. Mazzarello, S. Paolini, A. Pasquarello, L. Paulatto, C. Sbraccia, S. Scandolo, G. Sclauzero, A. P. Seitsonen, A. Smogunov, P. Umari, R. M. Wentzcovitch, QUANTUM ESPRESSO: a modular and open-source software project for quantum simu-lations of materials. J. Phys. Condens. Matter2009, 21, 395502.10.1088/0953-8984/21/39/395502Search in Google Scholar PubMed

[29] P. Ectors, D. Zahn, Analysis of the molecular interactions governing the polymorphism of benzamide – a guide to syntheses? Phys. Chem. Chem. Phys.2013, 15, 9219.10.1039/c3cp44279aSearch in Google Scholar PubMed

[30] K. E. Johansson, J. van de Streek, Revision of the crystal structure of the first molecular polymorph in history. Cryst. Growth Des.2016, 16, 1366.10.1021/acs.cgd.5b01495Search in Google Scholar

[31] W. I. F. David, K. Shankland, C. R. Pulham, N. Blagden, R. J. Davey, M. Song, Polymorphism in benzamide. Angew. Chem. Int. Edit.2005, 44, 7032.10.1002/anie.200501146Search in Google Scholar PubMed

[32] P. Ectors, P. Duchstein, D. Zahn, Nucleation mechanisms of a polymorphic molecular crystal: solvent-dependent structural evolution of benzamide aggregates. Cryst. Growth Des.2014, 14, 2972.10.1021/cg500247cSearch in Google Scholar

[33] J. Anwar, D. Zahn, Uncovering molecular processes in crystal nucleation and growth by using molecular simulation. Angew. Chem. Int. Ed.2011, 50, 1996.10.1002/anie.201000463Search in Google Scholar

[34] A. Kawska, J. Brickmann, R. Kniep, O. Hochrein, D. Zahn, An atomistic simulation scheme for modeling crystal formation from solution. J. Chem. Phys.2006, 124, 024513.10.1063/1.2145677Search in Google Scholar

[35] P. Ectors, P. Duchstein, D. Zahn, From oligomers towards a racemic crystal: molecular simulation of DL -norleucine crystal nucleation from solution. CrystEngComm.2015, 17, 6884.10.1039/C4CE02078BSearch in Google Scholar

[36] P. Ectors, J. Anwar, D. Zahn, Two-step nucleation rather than self-poisoning: an unexpected mechanism of asymmetrical molecular crystal growth. Cryst. Growth Des.2015, 15, 5118.10.1021/acs.cgd.5b01082Search in Google Scholar

[37] T. Milek, P. Duchstein, G. Seifert, D. Zahn, Motif reconstruction in clusters and layers: benchmarks for the kawska-zahn approach to model crystal formation. ChemPhysChem.2010, 11, 847.10.1002/cphc.200900907Search in Google Scholar

[38] J. Bernstein, R. J. Davey, J.-O. Henck, Concomitant polymorphs. Angew. Chem. Int. Ed.1999, 38, 3440.10.1002/(SICI)1521-3773(19991203)38:23<3440::AID-ANIE3440>3.0.CO;2-#Search in Google Scholar

[39] J. Thun, L. Seyfarth, C. Butterhof, J. Senker, R. E. Dinnebier, J. Breu, Wöhler and Liebig revisited: 176 years of polymorphism in benzamide – and the story still continues! †. Cryst. Growth Des.2009, 9, 2435.10.1021/cg801347dSearch in Google Scholar

[40] T. Furuhara, T. Maki, Variant selection in heterogeneous nucleation on defects in diffusional phase transformation and precipitation. Mater. Sci. Eng. A2001, 312, 145.10.1016/S0921-5093(00)01904-3Search in Google Scholar

[41] V. I. Levitas, B. F. Henson, L. B. Smilowitz, B. W. Asay, Solid-solid phase transformation via virtual melting significantly below the melting temperature. Phys. Rev. Lett.2004, 92, 235702.10.1103/PhysRevLett.92.235702Search in Google Scholar

[42] H. G. Brittain, Vibrational spectroscopic studies of cocrystals and salts. 1. The benzamide–benzoic acid system. Cryst. Growth Des.2009, 9, 2492.10.1021/cg801397tSearch in Google Scholar

[43] C. C. Seaton, A. Parkin, Making benzamide cocrystals with benzoic acids: the influence of chemical structure. Cryst. Growth Des.2011, 11, 1502.10.1021/cg101403jSearch in Google Scholar

[44] M. H. Levitt, D. M. Grant, R. K. Harris, J. Wiley, Symmetry-Based Pulse Sequences in Magic-Angle Spinning Solid-State NMR, 2002.10.1002/chin.200338276Search in Google Scholar

[45] M. Schmidt, J. J. Wittmann, R. Kress, H. Schmidt, J. Senker, Probing self-assembled 1,3,5-benzenetrisamides in isotactic polypropylene by 13C DQ solid-state NMR spectroscopy, Chem. Commun. 2013, 49, 267.10.1039/C2CC37384JSearch in Google Scholar

[46] T. Gullion, J. Schaefer, Rotational-echo double-resonance NMR. J. Magn. Reson.2011, 213, 413.10.1007/1-4020-3910-7_89Search in Google Scholar

[47] T. Gullion, Introduction to rotational-echo, double-resonance NMR. Concepts Magn. Reson. 1998, 10, 277.10.1002/(SICI)1099-0534(1998)10:5<277::AID-CMR1>3.0.CO;2-USearch in Google Scholar

[48] M. Bak, J. T. Rasmussen, N. C. Nielsen, SIMPSON: a general simulation program for solid-state NMR spectroscopy. J. Magn. Reson.2000, 147, 296.10.1006/jmre.2000.2179Search in Google Scholar

[49] A. L. Rohl, D. M. P. Mingos, The size and shape of molecular ions and their relevance to the packing of the hexafluorophosphate salts. J. Chem. Soc. Dalt. Trans.1992, 3541.10.1039/dt9920003541Search in Google Scholar

[50] E. Lück, Chemical preservation of food. Zentralblatt für Bakteriol. Mikrobiol. und Hyg. 1. Abt. Orig. B, Hyg.1985, 180, 311.Search in Google Scholar

[51] R. Van Deun, J. Ramaekers, P. Nockemann, K. Van Hecke, L. Van Meervelt, K. Binnemans, Alkali-metal salts of aromatic carboxylic acids: liquid crystals without flexible chains. Eur. J. Inorg. Chem.2005, 2005, 563.10.1002/ejic.200400394Search in Google Scholar

[52] C. Butterhof, T. Martin, W. Milius, J. Breu, Microphase separation with small amphiphilic molecules: crystal structure of preservatives sodium benzoate (E 211) and potassium benzoate (E 212). Z. Anorg. Allg. Chem.2013, 639, 2816.10.1002/zaac.201300436Search in Google Scholar

[53] T. W. Martin, T. E. Gorelik, D. Greim, C. Butterhof, U. Kolb, J. Senker, J. Breu, Microphase separation upon crystallization of small amphiphilic molecules: “low” temperature form II of sodium benzoate (E 211). CrystEngComm.2016, 18, 5811.10.1039/C6CE01281GSearch in Google Scholar

[54] L. Leibler, Theory of microphase separation in block copolymers. Macromolecules1980, 13, 1602.10.1021/ma60078a047Search in Google Scholar

[55] H. J. Flammersheim, Physikalisch-chemische Untersuchungen am system Natriumbenzoat/Benzoesäure (III) Untersuchungen an der Tieftemperaturmodifikation des Komplexes 1 Natriumbenzoat · 2 Benzoesäure. Krist. Und Tech.1974, 9, 313.10.1002/crat.19740090316Search in Google Scholar

[56] H. J. Flammersheim, Physikalisch-chemische Untersuchungen am system Natriumbenzoat/Benzoesäure (I) Infrarotspektropische und röntgenografische Untersuchungen bei Raumtemperatur. Krist. Und Tech.1974, 9, 299.10.1002/crat.19740090315Search in Google Scholar

[57] H. J. Flammersheim, Physikalisch-chemische Untersuchungen am system Natriumbenzoat/Benzoesäure. J. Therm. Anal.1975, 7, 571.10.1007/BF01912018Search in Google Scholar

[58] A. V. Trask, W. D. S. Motherwell, W. Jones, Solvent-drop grinding: green polymorph control of cocrystallisation. Chem. Commun.2004, 890.10.1039/b400978aSearch in Google Scholar PubMed

[59] C. Butterhof, W. Milius, J. Breu, Co-crystallisation of benzoic acid with sodium benzoate: the significance of stoichiometry. CrystEngComm.2012, 14, 3945.10.1039/c2ce25185jSearch in Google Scholar

[60] C. Butterhof, K. Bärwinkel, J. Senker, J. Breu, Polymorphism in co-crystals: a metastable form of the ionic co-crystal 2 HBz·1 NaBz crystallised by flash evaporation. CrystEngComm2012, 14, 6744.10.1039/c2ce25562fSearch in Google Scholar

[61] C. Butterhof, W. Milius, J. Breu, Influence of cation size on the co-crystallisation of benzoic acid with different benzoates. Z. Anorg. Allg. Chem.2013, 639, 308.10.1002/zaac.201200464Search in Google Scholar

[62] J. M. Skinner, G. M. D. Stewart, J. C. Speakman, The crystal structure of the acid salts of some monobasic acids. Part III. Potassium hydrogen dibenzoate. J. Chem. Soc.1954, 180.10.1039/jr9540000180Search in Google Scholar

Supplemental Material:

The online version of this article (DOI: 10.1515/zkri-2016-1977) offers supplementary material, available to authorized users.

Received: 2016-6-10
Accepted: 2016-8-2
Published Online: 2016-8-17
Published in Print: 2017-2-1

©2017 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Graphical Synopsis
  3. Editorial
  4. Synthesis and characterization of metastable transition metal oxides and oxide nitrides
  5. Control of organic polymorph formation: crystallization pathways in acoustically levitated droplets
  6. Thermal annealing of natural, radiation-damaged pyrochlore
  7. The formation of CdS quantum dots and Au nanoparticles
  8. Crystalline chalcogenido metalates – synthetic approaches for materials synthesis and transformation
  9. Fundamental theoretical and practical investigations of the polymorph formation of small amphiphilic molecules, their co-crystals and salts
  10. A density-functional theory approach to the existence and stability of molybdenum and tungsten sesquioxide polymorphs
  11. The ZIF system zinc(II) 4,5-dichoroimidazolate: theoretical and experimental investigations of the polymorphism and crystallization mechanisms
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https://doi.org/10.1515/zkri-2016-1977
Keywords for this article
amphiphilic molecules; benzamide; benzoate; benzoic acid; co-crystal; crystal structure; polymorphism

Articles in the same Issue

  1. Frontmatter
  2. Graphical Synopsis
  3. Editorial
  4. Synthesis and characterization of metastable transition metal oxides and oxide nitrides
  5. Control of organic polymorph formation: crystallization pathways in acoustically levitated droplets
  6. Thermal annealing of natural, radiation-damaged pyrochlore
  7. The formation of CdS quantum dots and Au nanoparticles
  8. Crystalline chalcogenido metalates – synthetic approaches for materials synthesis and transformation
  9. Fundamental theoretical and practical investigations of the polymorph formation of small amphiphilic molecules, their co-crystals and salts
  10. A density-functional theory approach to the existence and stability of molybdenum and tungsten sesquioxide polymorphs
  11. The ZIF system zinc(II) 4,5-dichoroimidazolate: theoretical and experimental investigations of the polymorphism and crystallization mechanisms
  12. Element allotropes and polyanion compounds of pnicogenes and chalcogenes: stability, mechanisms of formation, controlled synthesis and characterization
  13. Structure and ion dynamics of mechanosynthesized oxides and fluorides
  14. Scaled-up solvothermal synthesis of nanosized metastable indium oxyhydroxide (InOOH) and corundum-type rhombohedral indium oxide (rh-In2O3)
  15. Development and application of novel NMR methodologies for the in situ characterization of crystallization processes of metastable crystalline materials
  16. Phase formation and stability in TiOx and ZrOx thin films: Extremely sub-stoichiometric functional oxides for electrical and TCO applications
  17. Investigations on the growth of bismuth oxido clusters and the nucleation to give metastable bismuth oxide modifications
  18. Divalent metal phosphonates – new aspects for syntheses, in situ characterization and structure solution
  19. Type-I silicon clathrates containing lithium
  20. Experimental and theoretical investigation of the chromium–vanadium–antimony system
  21. Synthesis and crystal structure of three new bismuth(III) arylsulfonatocarboxylates
  22. Snapshots of calcium carbonate formation – a step by step analysis
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