Modifying Pharmaceutical Properties of Levofloxacin by Crystal Engineering

Abstract

The commercial form of a fluoroquinolone antibiotic, levofloxacin (Lev), is a hydrochloride salt (Lev-HCl). Lev-HCl possesses an intense bitter taste, which presents a challenge for developing an oral tablet with high patient compliance. We approached this challenge by preparing a sweet salt of Lev with an artificial sweetener, Acesulfame (Acs), through an anion exchange reaction. Solid-state properties of an anhydrous Lev-Acs salt were characterized using various analytical techniques. With a degradation temperature at about 260 °C, Lev-Acs is thermally more stable than Lev-HCl. Lev-Acs also exhibits approximately 3 orders of magnitude lower aqueous solubility than Lev-HCl. Both the lower aqueous solubility and the presence of a sweetener make Lev-Acs an excellent candidate for taste-masking. Lev-Acs exhibits superior tabletability at pressures below 150 MPa, attributed to its high plasticity. The results suggest that Lev-Acs holds promise for formulating a palatable tablet, addressing challenges associated with Lev-HCl. Based on analysis of five pairs of stoichiometric hydrates and corresponding anhydrates, it was hypothesized that higher plasticity of a hydrate is caused by a lower crystal packing efficiency and density. In these systems, all hydrates exhibit higher plasticity and lower packing efficiency. Thus, an example of a hydrate with a higher packing efficiency exhibiting lower plasticity would strengthen this hypothesis. Ideally, this can be observed for channel hydrates, where filling the channel space by water molecules increases crystal packing efficiency. In the absence of such an ideal model system, we have tested this hypothesis using a channeled hemi-methanol solvate of a levofloxacin acesulfame salt. Our results confirm this hypothesis since, compared to the isostructural anhydrate, the hemi-methanol solvate exhibits higher packing efficiency and lower plasticity. The higher plasticity of the solvate is confirmed by both crystal structure analysis and energy framework calculations. If this correlation between crystal packing efficiency and plasticity is robust, we can objectively predict material plasticity of structurally related crystals based on crystal packing efficiency.