Single-crystal diffuse scattering studies on polymorphs of molecular crystals. I. The room-temperature polymorphs of the drug benzocaine

Abstract

The drug benzocaine (ethyl 4-aminobenzoate), commonly used as a local anaesthetic, is a bimorphic solid at room temperature. Form (I) is monoclinic P2(1)/c, while the metastable form (II) is orthorhombic P2(1)2(1)2(1). Three-dimensional diffuse X-ray scattering data have been collected for the two forms on the 11-ID-B beamline at the Advanced Photon Source (APS). Both forms show strong and highly structured diffuse scattering. The data have been interpreted and analysed using Monte Carlo (MC) modelling on the basis that the scattering is purely thermal in origin and indicates the presence of highly correlated molecular motions. In both forms (I) and (II) broad diffuse streaks are observed in the 0kl section which indicate strong longitudinal displacement correlations between molecules in the 031 directions, extending over distances of up to 50 A. Streaks extending between Bragg peaks in the hk0 section normal to [100] correspond to correlated motions of chains of molecules extending along a that are linked by N-H...O=C hydrogen bonds and which occur together as coplanar ribbon pairs. The main difference between the two forms is in the dynamical behaviour of the ribbon pairs and in particular how they are able to slide relative to each other. While for form (I) a model involving harmonic springs is able to describe the motion satisfactorily, as simple excursions away from the average structure, there is evidence in form (II) of anharmonic effects that are precursors of a phase transition to a new low-temperature phase, form (III), that was subsequently found.

Synchrotron X-ray diffuse scattering from a stable polymorphic material: terephthalic acid, C8H6O4

“…This is in accordance with the fact that, although TPA is polymorphic, at the measurement temperature 295 K, and polymorphs are stable, polymorph (I) will transform into (II) with heating. This implies there is an anharmonicity that increases with T until significant enough to trigger the phase transition, but is present in some small degree at 295 K. Polymorphic benzocaine [polymorph (II)] and aspirin [polymorph (II)] both showed nonharmonic aspects to the scattering due to an incipient phase transition and to correlated defects, respectively (Chan, 2015;Chan et al, 2009;, neither of these mechanisms is apparent in either triclinic polymorph of TPA at room temperature. In this it is similar to paracetamol, which also showed scattering that could be modelled harmonically (Chan & Goossens, 2012).…”

“…However, the agreement with experiment was not improved by allowing torsional motions, or by any other harmonic motion of the molecule or its parts. It is therefore suggested, following previous work (Chan et al, 2009;Chan & The chains of hydrogen bonds (thick black lines) running along a þ b in polymorph (I) of TPA. Dummy atoms, added to simplify simulation but not included in the Fourier transform, are shown (in green) in the centres of the phenyl rings.…”

Monte Carlo Modeling of Diffuse Scattering from Single Crystals: The Program ZMC

“…(12) Refine the MC parameters accordingly, whether manually or through some automatic process. [5,15,16,19,20] Note that this may entail developing new classes of contact vectors, or even changing the definition of the z-matrix if it becomes apparent that the molecule must be allowed a motion that the current definition prohibits. (13) When a satisfactory agreement is reached, explore the model crystal to directly examine its SRO, on the understanding that the SRO in the model reflects that in the real crystal.…”

“…ZMC [18] is an attempt to produce a program that can deal with a significant subset of the possible types of SRO without the need for custom-written code for tackling each problem. The program has been used in several published studies, [5,15,[19][20][21][22][23] all centering on flexible molecular crystals, some with purely displacive disorder (thermal motion) and some with displacements and occupancy disorder.…”

Polymorphism and Solvatomorphism 2009

“…42 The structures of two polymorphs of benzocaine have been reported, with Form-I crystallizing in the monoclinic P2 1 /c space group, and the metastable Form-II crystallizing in the noncentrosymmetric orthorhombic P2 1 2 1 2 1 space group. 43 It is interesting to note that even though benzocaine is achiral, by virtue of its crystal structure, individual crystals of Form-II would be expected to exhibit optical activity. The polymorphic space of benzocaine was shown to be more complicated in that a low-temperature structural phase transition was reported for benzocaine Form-II, which resulted in a doubling of the b-axis repeat and a consequent change in space group from P2 1 2 1 2 1 to P112 1 .…”