Polymorphism in S(+)Clopidogrel-Picrate: Insights from X-ray Diffraction, Vibrational Spectroscopy, Thermal Analysis, and Quantum Chemistry

Aleksandar Cvetkovski; Petre Makreski; Ljupcho Pejov; Monika Stojanovska Pecova; Valerio Bertolasi; Paola Gilli; Leonard R. MacGillivray

doi:10.3390/cryst14010010

$Polymorphism in S(+)Clopidogrel-Picrate: Insights from X-ray Diffraction, Vibrational Spectroscopy, Thermal Analysis, and Quantum Chemistry$

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Polymorphism in S(+)Clopidogrel-Picrate: Insights from X-ray Diffraction, Vibrational Spectroscopy, Thermal Analysis, and Quantum Chemistry

Aleksandar Cvetkovski, Petre Makreski, Ljupcho Pejov, Monika Stojanovska Pecova, Valerio Bertolasi, Paola Gilli and Leonard R. MacGillivray

Crystals (Basel), Vol.14(1), 10

12/22/2023

DOI: 10.3390/cryst14010010

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Abstract

The crystal structures of two pseudopolymorphic forms of S(+)clopidogrel–picrate are reported. Form 1 crystallizes in the monoclinic space group P21 with an ionic couple S(+)ClopH+·Pic− and a molecule of solvent ethanol in the asymmetric unit, while Form 2 crystallizes in the monoclinic space group C2 with two ionic couples in the asymmetric unit. The configurations and conformations of the ionic couples, held together by ionized +N-H···O hydrogen bonds, are nearly identical in the structures. The self-assembly properties are compared with reported clopidogrel salts, including those used in pharmaceutical formulations. The hydrogen bonds are discussed in reference to the general corresponding behavior of the N-bases picrates and the properties of the acid-base coformers. The preparations of the pseudopolymorphs were optimized toward two different methods: solvent evaporation and mechanochemical treatment. Reproducibility to generate the single crystalline phases was confirmed by thermal and vibrational spectroscopic properties. Periodic third-order density-functional tight binding (DFTB3) calculations predict rather small energy difference between the two pure phases of polymorphs 1 and 2. However, the included solvent molecules in Form 1 decrease the lattice energy for ~10.5 kcal mol−1, which leads to a lower ΔElatt. lattice energy in comparison to Form 2 (by ~7.3 kcal mol−1). All predicted trends are in line with the experimentally observed formation of Form 1 instead of its simulated non-solvated Form 1.

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Title: Subtitle: Polymorphism in S(+)Clopidogrel-Picrate: Insights from X-ray Diffraction, Vibrational Spectroscopy, Thermal Analysis, and Quantum Chemistry
Creators: Aleksandar Cvetkovski - Goce Delcev University
Petre Makreski - Ss. Cyril and Methodius University in Skopje
Ljupcho Pejov
Monika Stojanovska Pecova
Valerio Bertolasi - University of Ferrara
Paola Gilli - University of Ferrara
Leonard R. MacGillivray - University of Iowa
Resource Type: Journal article
Publication Details: Crystals (Basel), Vol.14(1), 10
DOI: 10.3390/cryst14010010
ISSN: 2073-4352
eISSN: 2073-4352
Language: English
Date published: 12/22/2023
Academic Unit: Chemistry
Record Identifier: 9984539445102771

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