(M1130-11-64) Decreased Crystal Plasticity by Solvation-The Case of Levofloxacin Acesulfame

Purpose: Based on an analysis of five anhydrate-hydrate pairs, it was recently hypothesized that a lower crystal packing efficiency corresponds to higher crystal plasticity (Wang et al., 2022). Since all those hydrates exhibited higher plasticity and lower packing efficiency in that study, an example of a hydrate (or solvate) with a higher packing efficiency exhibiting lower plasticity would strengthen the hypothesis. The goal of this work was to test this hypothesis using a channeled hemi-methanol solvate of a levofloxacin acesulfame salt, where methanol molecules increase crystal packing efficiency by filling the channel space.  A structurally similar crystal with a higher molecular packing efficiency is expected to have a stronger lattice and lower plasticity because closer packing leads to stronger intermolecular interactions and more resistance to slip between layers when sheared.

Methods: Levofloxacin acesulfame anhydrate (Lev-Acs, Figure 1) was synthesized using levofloxacin hydrochloride and acesulfame potassium in water through an efficient anion exchange reaction (Wang et al., 2018). Lev-Acs hemi-methanol solvate (Lev-Acs)(MeOH)_0.5  was obtained by cooling a hot Lev-Acs solution in methanol to room temperature. Crystal structures of both the anhydrate and the hemi-methanol solvate were solved by single crystal X-ray diffraction. Phase purity of powders was established by comparing experimental PXRD patterns to those calculated from corresponding crystal structures. We used helium pycnometry to measure the true density of Lev-Acs. A buoyancy method was used to measure the true density of (Lev-Acs)(MeOH)_0.5 , since the release of methanol in a dry helium atmosphere causes errors in density value measured by helium pycnometry. The value of in-die mean yield pressure, P_y,i, was obtained from Heckel analysis of in-die compaction data porosity and pressure data collected using a compaction simulator (Vreeman et al., 2021). The crystal structures of both (Lev-Acs)(MeOH)_0.5 and Lev-Acs were systematically analyzed using complementary techniques. Crystal structure visualization using Mercury identified possible slip planes, which were then confirmed by their energy frameworks, obtained by calculating pairwise intermolecular interaction energies using CrystalExplorer 17 (Turner et al., 2017). Pair-wised interaction energy was calculated using a dispersion-corrected density functional theory at the B3LYP/6-31 G(d,p) level of theory. Interlayer interaction energies were obtained by summing up interaction energies between a given molecule in one layer and all interacting molecules in a neighboring layer.

Results: Single crystal X-ray diffraction revealed that the unit cell parameters of (Lev-Acs)(MeOH)_0.5 and Lev-Acs are closely similar (Table 1), implying similar crystal structures. Close examination of the packing patterns confirmed similarity of the two structures, where both crystals feature parallel layers of Lev-Acs parallel to (001). Insertion of methanol molecules in the (Lev-Acs)(MeOH)_0.5 structure induces a small slide between adjacent Lev-Acs layers along the < 100 > direction and slight expansion along the < 010 > direction (Figure 2a,c). Based on the P_y,i values, (LevAcs)(MeOH)_0.5 (95.40±1.60 MPa) is less plastic than Lev-Acs (86.74±1.17 MPa). Compared to Lev-Acs, (LevAcs)(MeOH)_0.5 also exhibited higher packing efficiency and higher density (Table 2). These findings support the hypothesis that solid forms of a compound with higher packing efficiency tend to be less plastic. The slip layers in both crystals are parallel to (001) planes (shaded in pink in Figure 2a, 2c). These layers are fortified by strong π···π interactions among closely stacking levofloxacin molecules, leading to strongest overall intermolecular interaction (indicated by the thickest blue cylinders in the energy frameworks) (Figure 2b, 2d). The interaction energy between the slip layers in (Lev-Acs)(MeOH)_0.5 (-24.15 kJ/mol) is significantly stronger than that in the anhydrate (-12.2 kJ/mol), which corroborates the observed lower plasticity of (Lev-Acs)(MeOH)_0.5 than the anhydrate.

Conclusion: The correlation between crystal packing efficiency and plasticity is confirmed by structurally similar (LevAcs)(MeOH)_0.5 and Lev-Acs, where the less plastic (LevAcs)(MeOH)_0.5 also exhibits higher packing efficiency and density. The lower plasticity of (LevAcs)(MeOH)_0.5 is attributed to the significantly stronger interaction between adjacent slip layers.  The correlation between plasticity and crystal packing efficiency suggests the possibility of rank ordering plasticity of crystal forms of a given compound from an analysis of crystal structures.

References: Goldenberg, M., Vreeman, G., Sun, D.J., Moffit, M., Li, M., Zernik, M., Ahuja, S., Kim, Y., Semin, D., Sun, C.C., 2023. A material-sparing simplified buoyancy method for determining the true density of solids. International Journal of Pharmaceutics 635, 122694.
Turner, M., McKinnon, J., Wolff, S., Grimwood, D., Spackman, P., Jayatilaka, D., Spackman, M., 2017. CrystalExplorer17. The University of Western Australia Australia.
Vreeman, G., Sun, C.C., 2021. Mean yield pressure from the in-die Heckel analysis is a reliable plasticity parameter. Int J Pharm X 3, 100094.
Wang, C., Perumalla, S.R., Sun, C.C., 2018. Anion Exchange Reaction for Preparing Acesulfame Solid Forms. Crystal Growth & Design 18, 4215-4219.
Wang, C., Sun, C.C., 2022. Mechanisms of Crystal Plasticization by Lattice Water. Pharmaceutical Research 39, 3113-3122.


Figure 1. Molecular structure of Lev-Acs (MW = 524.52 g/mol)


Table 1. Key crystallographic parameters of Lev-Acs and (Lev-Acs)(MeOH)0.5.
Table 2. Comparison of key properties of Lev-Acs anhydrate and hemi-methanol solvate (Lev-Acs)(MeOH)0.5.


Figure 2. Crystal packing and corresponding energy frameworks for (a,b) Lev-Acs anhydrate and (c,d) Lev-Acs hemi-methanol solvate viewed into the b-axis. A slip layer is highlighted in pink.