Exploring the CSD Drug Subset: An Analysis of Lattice Energies and Constituent Intermolecular Interactions for the Crystal Structures of Pharmaceuticals

Cai, Yuanqiang; Moldovan, Alexandru A.; Maloney, A. F. J.

doi:10.1016/j.xphs.2022.11.027

Cited by 8 publications

(6 citation statements)

References 49 publications

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“…This suggests a conformational change of energy penalty associated with crystallization albeit only a small one with a < 1.8 kcal/mol difference in the conformational energies of all calculated conformations, indicating overall that the crystal packing considerations would be expected to be dominant in the crystal structural energy balance. This is consistent with the behavior of many small molecule pharmaceuticals . The torsion angles involving CN group for the form A molecule and two form D molecules have differences about 40°, indicating similar exposure and availability of CN group for all three molecular conformers.…”

Section: Results and Discussionsupporting

confidence: 84%

“…This is consistent with the behavior of many small molecule pharmaceuticals. 25 The torsion angles involving CN group for the form A molecule and two form D molecules have differences about 40°, indicating similar exposure and availability of CN group for all three molecular conformers. Further details can be found in the Supporting Information, Section S3.…”

Section: Molecular Chemistry Analysis Of Entacaponementioning

confidence: 94%

“…could be changed by modifying the structure and interfacial properties of the templates, e.g., using single crystals of metals such as gold, 13 organic crystals, 1,8,14 polymers, 15−17 Langmuir monolayers, 5 and surface-assembled monolayers. 18−20 A well-characterized example of templating has been provided by the pharmaceutical compound entacapone 2,6,7,21 which is important in the treatment of Parkinson's disease, 22,23 and one that also meets the "Lipinski rule of 5" 24 criteria for its representative molecular and crystallographic parameters 25 within the pharmaceutical drug subset. 26 Entacapone has two well-characterized polymorphic forms (A and D), each of which have distinctly different crystal structures, external morphologies and crystallization behavior.…”

Section: Introductionmentioning

confidence: 99%

“…A well-characterized example of templating has been provided by the pharmaceutical compound entacapone ,,, which is important in the treatment of Parkinson’s disease, , and one that also meets the “Lipinski rule of 5” criteria for its representative molecular and crystallographic parameters within the pharmaceutical drug subset . Entacapone has two well-characterized polymorphic forms (A and D), each of which have distinctly different crystal structures, external morphologies and crystallization behavior .…”

Section: Introductionmentioning

confidence: 99%

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Role of Molecular, Crystal, and Surface Chemistry in Directing the Crystallization of Entacapone Polymorphs on the Au(111) Template Surface

Geatches

Hsiao

et al. 2023

Crystal Growth & Design

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The pharmaceutical compound entacapone ((E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylprop-2-enamide) is important in the treatment of Parkinson’s disease, exhibiting interesting polymorphic behavior upon crystallization from solution. It consistently produces its stable form A with a uniform crystal size distribution on the surface of an Au(111) template while concomitantly forming its metastable form D within the same bulk solution. Molecular modeling using empirical atomistic force-fields reveals more complex molecular and intermolecular structures for form D compared to form A, with the crystal chemistry of both polymorphs being dominated by van der Waals and π–π stacking interactions with lower contributions (ca. 20%) from hydrogen bonding and electrostatic interactions. Comparative lattice energies and convergence for the polymorphs are consistent with the observed concomitant polymorphic behavior. Synthon characterization reveals an elongated needle-like morphology for form D crystals in contrast to the more equant form A crystals with the surface chemistry of the latter exposing the molecules’ cyano groups on its {010} and {011} habit faces. Density functional theory modeling of surface adsorption reveals preferential interactions between Au and the synthon GA interactions of form A on the Au surface. Molecular dynamics modeling of the entacapone/gold interface reveals the entacapone molecular structure within the first adsorbed layer to show nearly identical interaction distances, for both the molecules within form A or D with respect to the Au surface, while in the second and third layers when entacapone molecule–molecule interactions overtake the interactions between those of molecule–Au, the intermolecular structures are found to be closer to the form A structure than form D. In these layers, synthon GA (form A) could be reproduced with just two small azimuthal rotations (5° and 15°) whereas the closest alignment to a form D synthon requires larger azimuthal rotations (15° and 40°). The cyano functional group interactions with the Au template dominate interfacial interactions with these groups being aligned parallel to the Au surface and with nearest neighbor distances to Au atoms more closely matching those in form A than form D. The overall polymorph direction pathway thus encompasses consideration of molecular, crystal, and surface chemistry factors.

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Section: Results and Discussionsupporting

confidence: 84%

Section: Molecular Chemistry Analysis Of Entacaponementioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Role of Molecular, Crystal, and Surface Chemistry in Directing the Crystallization of Entacapone Polymorphs on the Au(111) Template Surface

Geatches

Hsiao

et al. 2023

Crystal Growth & Design

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“…The crystal morphology is modeled by the attachment energy [ 20 ]. Roberts et al used HABIT98 software to study lattice energies and constituent intermolecular interactions for the crystal structures of pharmaceuticals [ 21 ]. The program Mercury, developed at the Cambridge Crystallographic Data Centre, has become a powerful platform delivering analysis, design, and prediction functionality alongside visualization for crystal structure [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

The Effect of Solvents on the Crystal Morphology of Isosorbide Mononitrate and Its Molecular Mechanisms

Li,

Zhang,

Zhou

et al. 2024

Molecules

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In this work, the modified attachment energy model was used to predict the crystal morphology of isosorbide mononitrate (ISMN) in the dichloromethane (CH2Cl2) solvent system and dichloromethane-n-hexane (CH2Cl2-C6H14) mixed solvent system. The solvent effect can significantly affect the crystal morphology, which can profoundly impact both the drug’s physicochemical properties and the subsequent technological treatment process. In addition, the interactions between solvent molecules and crystal faces were investigated using molecular dynamics simulation, and radial distribution function (RDF) analysis was performed to determine the types of interactions. The structural parameter S was introduced to characterize the roughness of each crystal surface; the change in the CH2Cl2 diffusion coefficient before and after the addition of C6H14 was analyzed using mean square displacement (MSD). The calculation results of the modified attachment energy from the two solvent systems revealed that C6H14 could accelerate crystal growth, while the crystal morphology was not greatly affected, which is of some significance as a guide for the industrial crystallization process.

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Predicting particle quality attributes of organic crystalline materials using Particle Informatics

Prandini,

Calì,

Maloney

et al. 2024

Powder Technology

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Exploring the CSD Drug Subset: An Analysis of Lattice Energies and Constituent Intermolecular Interactions for the Crystal Structures of Pharmaceuticals

Cited by 8 publications

References 49 publications

Role of Molecular, Crystal, and Surface Chemistry in Directing the Crystallization of Entacapone Polymorphs on the Au(111) Template Surface

Role of Molecular, Crystal, and Surface Chemistry in Directing the Crystallization of Entacapone Polymorphs on the Au(111) Template Surface

The Effect of Solvents on the Crystal Morphology of Isosorbide Mononitrate and Its Molecular Mechanisms

Predicting particle quality attributes of organic crystalline materials using Particle Informatics

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