Improving Mechanical Properties of Crystalline Solids by Cocrystal Formation: New Compressible Forms of Paracetamol

Karki, Shyam; Friščić, Tomislav; Fábián, László; Laity, Peter R.; Day, Graeme M.; Jones, William

doi:10.1002/adma.200900533

Cited by 465 publications

(413 citation statements)

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“…To investigate the interaction driving solid-state complexation we pursued single crystal X-ray diffraction structure analysis. Suitable single crystals were grown from solution for the cocrystals of pro with 4-bromophenol (2), pyrenol (12), 9-phenanthrol (13), 2,7-dihydroxynaphthalene (14), gentisic acid (15), phenanthrene (21), and pyrene (22). The cocrystals of pre with 2-naphthol (5) and of bes with pyrene (22) were also structurally characterized using single crystal X-ray diffraction, whereas the structure of (pre).…”

Section: Resultsmentioning

confidence: 99%

“…We have selected steroids as model systems due to their prominent role in life sciences and their well-established use as pharmacophores. Whereas the formation of steroid hydrates and solvates is well-established (18) and cocrystallization of steroids has been proposed as a means to improve properties of pharmaceuticals (19)(20)(21), solid-state complexation of steroids with aromatic molecules has never been systematically studied. The exception is the work of Eger and Norton (22) who employed cocrystallization with 4-bromophenol to determine the steroid backbone stereochemistry using the heavy atom method (18,22,23).…”

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confidence: 99%

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Tunable recognition of the steroid α-face by adjacent π-electron density

Friščić

Lancaster

Fábián

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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We report a previously unknown recognition motif between the α-face of the steroid hydrocarbon backbone and π-electron-rich aromatic substrates. Our study is based on a systematic and comparative analysis of the solid-state complexation of four steroids with 24 aromatic molecules. By using the solid state as a medium for complexation, we circumvent solubility and solvent competition problems that are inherent to the liquid phase. Characterization is performed using powder and single crystal X-ray diffraction, infrared solid-state spectroscopy and is complemented by a comprehensive cocrystal structure prediction methodology that surpasses earlier computational approaches in terms of realism and complexity. Our combined experimental and theoretical approach reveals that the α⋯π stacking is of electrostatic origin and is highly dependent on the steroid backbone's unsaturated and conjugated character. We demonstrate that the α⋯π stacking interaction can drive the assembly of molecules, in particular progesterone, into solid-state complexes without the need for additional strong interactions. It results in a marked difference in the solid-state complexation propensities of different steroids with aromatic molecules, suggesting a strong dependence of the steroid-binding affinity and even physicochemical properties on the steroid's A-ring structure. Hence, the hydrocarbon part of the steroid is a potentially important variable in structure-activity relationships for establishing the binding and signaling properties of steroids, and in the manufacture of pharmaceutical cocrystals.steroids | molecular recognition | mechanosynthesis | crystal structure prediction A wide variety of tools, including site-directed mutagenesis (1), binding and inhibition screening (2-4), computational modeling (5), and protein crystallography (6, 7) are commonly used in studying the interaction of biologically important molecules, such as steroids, with their respective receptor binding domains (8). Molecular recognition can also be effectively probed using the considerably simpler and inexpensive methodology of forming crystalline molecular complexes (9) (multicomponent crystals, also known as cocrystals). Similarly to binding on synthetic model receptors (10, 11), solid-state complexation with small molecules (cocrystallization) offers the possibility to separately screen and deconvolute a far larger space of molecular recognition motifs (12) that collectively account for the biological activity. However, formation of solid-state complexes from solution is not a reliable measure of molecular affinity due to the vexatious problems of solubility and solvent competition. Mechanosynthesis, in the form of liquid-assisted grinding (LAG) (13), avoids these adverse effects and offers the possibility to systematically explore molecular recognition in the solid state (14,15).The rationalization of statistical data from structure-activity binding (16) or cocrystallization studies (17) is often based on qualitative and intuitive arguments and an establ...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Tunable recognition of the steroid α-face by adjacent π-electron density

Friščić

Lancaster

Fábián

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…There are many examples of significant improvements of API behaviors both in vivo and in vitro [14,15] due to enhancement of pharmacokinetic properties as solubility [4,16,17] and bioavailability [18][19][20]. Also many other physicochemical properties can be modulated by cocrystallization including stability [21][22][23][24], hygroscopicity [25] and prolonged shelf life [26]. Among many drugs, aromatic amides acting either as APIs or as excipients attract nowadays substantial attention [27][28][29][30][31][32][33][34][35].…”

Section: Introductionmentioning

confidence: 99%

Transferability of cocrystallization propensities between aromatic and heteroaromatic amides

Cysewski

2016

Struct Chem

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New virtual cocrystal screening was proposed taking advantage of the similarities between cocrystallization landscapes of different compounds. Assuming that cocrystallization propensities can be modeled by miscibility affinities of liquid components under supercooled conditions, the quantitative rules of likeness were formulated and validated for 45 aromatic and heteroaromatic amides interacting with a variety of coformers. The most important finding comes from the observed linear trends between the values of mixing enthalpies of amides with respect to a reference molecule. Particularly isonicotinamide was found as a very convenient comparative system since it constitutes 97 binary cocrystals. Many experimentally observed cocrystals were used for supporting the analogy hypothesis, which states that a properly selected reference molecule, for which cocrystals were experimentally documented, can provide practical information about cocrystallization propensities of another compound provided that two criterions are met, namely sufficiently high similarities and high enough affinities. Hence, it is not necessary to perform experimental cocrystallization of every pair of coformers since miscibility in the solid state of one compound can be transferred to another one at least in the case of aromatic or heteroaromatic amides.

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“…2 In addition, molecular crystals can also have a wide range of optical, electronic, and mechanical properties, 3 which in some cases can be tuned based on environmental variables 4 or composition. 5 The importance of molecular crystals has lead to various computational approaches being employed to understand and elucidate their properties. While crystal-structure prediction and pharmaceuticals are very active and important areas of research, 6,7 many computational studies have also focused on energetic materials, 8,9 proton-transfer systems, 4,10 vibrational properties such as phonons and thermal displacement parameters, 11,12 as well as electronic properties.…”

Section: Introductionmentioning

confidence: 99%

Understanding the role of vibrations, exact exchange, and many-body van der Waals interactions in the cohesive properties of molecular crystals

Reilly

Tkatchenko

2013

The Journal of Chemical Physics

284

496

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The development and application of computational methods for studying molecular crystals, particularly density-functional theory (DFT), is a large and ever-growing field, driven by their numerous applications. Here we expand on our recent study of the importance of many-body van der Waals interactions in molecular crystals [A. M. Reilly and A. Tkatchenko, J. Phys. Chem. Lett. 4, 1028 (2013)], with a larger database of 23 molecular crystals. Particular attention has been paid to the role of the vibrational contributions that are required to compare experiment sublimation enthalpies with calculated lattice energies, employing both phonon calculations and experimental heat-capacity data to provide harmonic and anharmonic estimates of the vibrational contributions. Exact exchange, which is rarely considered in DFT studies of molecular crystals, is shown to have a significant contribution to lattice energies, systematically improving agreement between theory and experiment. When the vibrational and exact-exchange contributions are coupled with a many-body approach to dispersion, DFT yields a mean absolute error (3.92 kJ/mol) within the coveted "chemical accuracy" target (4.2 kJ/mol). The role of many-body dispersion for structures has also been investigated for a subset of the database, showing good performance compared to X-ray and neutron diffraction crystal structures. The results show that the approach employed here can reach the demanding accuracy of crystal-structure prediction and organic material design with minimal empiricism. © 2013 AIP Publishing LLC. [http://dx

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Improving Mechanical Properties of Crystalline Solids by Cocrystal Formation: New Compressible Forms of Paracetamol

Cited by 465 publications

References 40 publications

Tunable recognition of the steroid α-face by adjacent π-electron density

Tunable recognition of the steroid α-face by adjacent π-electron density

Transferability of cocrystallization propensities between aromatic and heteroaromatic amides

Understanding the role of vibrations, exact exchange, and many-body van der Waals interactions in the cohesive properties of molecular crystals

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