X-ray Structural Studies of Lomeridine Dihydrochloride Polymorphs

Abstract

Two polymorphs (forms I and II) of lomeridine dihydrochloride (1-[bis(4-fluorophenyl)methyl]-4-(2,3,4-trimethoxybenzyl)piperazine dihydrochloride) were prepared and characterized by means of X-ray powder diffractometry, infrared spectroscopy (IR), thermal analysis, and moisture absorption equilibrium. The molecular structures and/or molecular conformations of the two polymorphs were determined by three-dimensional X-ray analysis. Each polymorph formed two hydrogen bonds between the two hydrochloric acids and the two nitrogen atoms of piperazine (N1, N4). In form I, the N1–chloride ion distance (2.98 Å) was almost same as the N4–chloride ion distance (2.99 Å). In form II, the N1–chloride ion distance (2.95 Å) was shorter than the N4–chloride ion distance (3.06 Å). The IR spectra showed an absorption band assigned to the NH stretching vibration of form I centered at 2361 and that of form II split into two peaks at 2186cm−1 and 2560cm−1. The differential thermal analysis (DTA) profiles showed that both form I and form II have an endothermic peak which would relate to the release of hydrochloric acid. The temperature of the peak in form I was higher than that in form II. The differences in the two hydrogen bond lengths of form II appear to be reflected in these IR and DTA profiles. The hygroscopic behavior of forms I and II was investigated at various relative humidities at 25°C. Form II has a constant molecular composition only between 20 and 51% relative humidity (RH). On the other hand, form I has an anhydrate form between 0 and 64% RH. Accordingly, form II is not appropriate for pharmaceutical preparations, in contrast to form I.