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

The crystal structures of two pseudopolymorphic forms of S(+)clopidogrel-picrate are reported. Form 1 crystallizes in the monoclinic space group P2(1) 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-HO 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 similar to 10.5 kcal mol(-1), which leads to a lower Delta E-latt. lattice energy in comparison to Form 2 (by similar to 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.