Thermal and X-ray powder diffraction structural characterization of two benfluorex hydrochloride polymorphs

Two polymorphic forms of benfluorex hydrochloride, phases I and II, were isolated as monophasic polycrystalline samples, and structurally characterized using ab initio X-ray powder diffraction methods and a global optimization strategy (simulated annealing). Form I crystallizes in monoclinic system, space group P21/n, with Z = 4, a = 21.0719(10) Å, b = 7.0563(4) Å, c = 14.8684(7) Å, β = 116.998(3)°, V = 1969.8(2) Å3, while Form II crystallizes in the orthorhombic space group Pbca, with Z = 8, a = 33.8031(2) Å, b = 15.1451(8) Å, c = 7.6138(6) Å, V = 3897.9(4) Å3. Crystals of Form I and Form II of benfluorex hydrochloride are based upon an ionic packing of protonated benfluorex molecules at the most basic site, the N1 atoms, and chloride anions. Form I shows the presence of μ-Cl ions, generating centrosymmetric dimers with a N2Cl2 moiety, while Form II contains antiparallel chains of C-H⋯O hydrogen-bonded molecules running along c axis. DSC and thermodiffractometric measurements showed that heating progressively Form II from ambient temperature to 160 °C causes a phase transition to the thermodynamically stable Form I, immediately followed by the sample melting, near 165 °C. Recrystallization directly to Form I is observed when the melt is cooled back to ambient temperature, with a significant hysteresis (this event being centered near 130 °C).