Pseudo-polymorphic forms of new molecular salts of the antiplated drug with thienopyridine structure S(+)Clopidogrel

Cvetkovski, Aleksandar and Bertolasi, Valerio and Gilli, Paola (2017) Pseudo-polymorphic forms of new molecular salts of the antiplated drug with thienopyridine structure S(+)Clopidogrel. In: Crystallization by Design, CF@BO2017, 4-6 June 2017, Bologna, Italy.

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After expiration in 2012 of the patent protection for the blockbuster drug Clopidogrel (Plavix®, Sanofi-Aventis), it has been challenging for drug manufacturers to launch generic forms with improved physicochemical properties and biopharmaceutical performances [1]. Therefore our aim was a cocrystallization screening by crystal engineering approach for new molecular salts of the more active and better tolerated form of clopidogrel, the dextrorotary isomer S(+)clopidogrel, followed by structural determination. Few structures of this drug exist so far in the Cambridge Structural Database (CSD v.5.35): the two polymorphs of S(+)clopidogrel hydrogen sulfate used in pharmaceutical formulations, orthorhombic form II (refcode FUQMOU) and monoclinic form I (FUQMOU01) [2,3], as well as the S(+)clopidogrel camphosulfonate (JASHUG) [4] and S(+)clopidogrel isopropylsulfate (YEXHOZ) [5].
The crystal structures of two new pseudo-polymorphic forms of S(+)clopidogrel-picrate salt obtained by co-crystallization are reported. Compound 1 (CDCC 1448941), prepared by treating clopidogrel hydrogen sulfate with picric acid, crystallizes in the monoclinic space group P21 with a ionic couple S(+)ClopH+•Pic- and a molecule of solvent ethanol in the A.U.. Crystals of Compound 2 (CDCC 1448942), grown dissolving clopidogrel free base and picric acid in a methanol/n-propanol mixture, crystallize in the monoclinic space group C2 with two ionic couples in the A.U.. The configurations and conformations of the ionic couples, held together by quite strong ionized +N─H•••O− hydrogen bonds (H-bonds), are almost identical in both crystals. The two compounds are compared with known structures of clopidogrel salts, including those used in pharmaceutical formulations, and the H-bonds discussed in reference to the general behavior of the N-bases-picrate H-bond and to the coformers acid-base properties. d(N∙∙∙O) contact distances are in the range 2.752-2.815 Å with calculated H-bond energy from 2.68 to 3.45 kcal mol-1 and ΔpKa of -4.26. These medium-strong H-bonds fit well the reported correlations among d(D∙∙∙A), EHB, and pKa [6] aimed to verify the validity of the pKa equalization principle [7-9].

Item Type: Conference or Workshop Item (Poster)
Subjects: Medical and Health Sciences > Basic medicine
Engineering and Technology > Chemical engineering
Natural sciences > Chemical sciences
Engineering and Technology > Materials engineering
Divisions: Faculty of Medical Science
Faculty of Natural and Technical Sciences
Depositing User: Aleksandar Cvetkovski
Date Deposited: 12 Dec 2019 11:44
Last Modified: 12 Dec 2019 11:44

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