Multinuclear solid state NMR investigation of two polymorphic forms of ciprofloxacin-saccharinate

GARRO LINCK YAMILA; CHATTAH ANA KARINA; GRAF ROBERT; ROMAÑUK CAROLINA BEATRIZ; OLIVERA MARÍA EUGENIA; MANZO RUBEN HILARIO; MONTI GUSTAVO ALBERTO; SPIESS HANS

Angra dos Reis

Encuentro; 13th Nuclear Magnetic Resonance Users Meeting; 2011

Nuclear Magnetic Resonance Users Association (AUREMN)

Multicomponent crystalline pharmaceutical solids, as for example complexes or salts, are usually developed to improve the pharmaceutical performance of a single organic molecule in terms of solubility, stability, bioavailability and/or organoleptic properties.(1,2) On the other hand, the phenomenon of polymorphism and its influence on the chemical and physical properties of molecular crystals is well known.(3) This is especially true for pharmaceutical compounds, where polymorphic changes in the drug can lead to significant effects on bioavailability. The present multicomponent compound is a new ciprofloxacin saccharinate recently obtained.(4) Ciprofloxacin (CIP), is a widely prescribed, broad-spectrum oral fluoroquinolone antibiotic approved for the treatment of several types of infections. Interestingly, ciprofloxacin saccharinate (CIP-SAC) can exist in two different polymorphic forms, CIP-SAC (I) and CIP-SAC (II).(5) 1H NMR spectra under very fast MAS were recorded for the three samples. The 1H-1H DQ MAS correlation spectrum of CIP-SAC (II) (Figure 2 (a)) shows strong autocorrelation peaks at DQ= 6.6 ppm and DQ= 15.4 ppm, corresponding to Pip-Pip and saccharine-saccharine correlations respectively. The close spatial proximity of aromatic proton sites from neighboring molecules can be directly observed in the 1H-1H DQ correlation spectrum of CIP-SAC (II). The DQ signal observed at DQ = 13.8 ppm = 7.2 + 6.6 ppm results from a DQ coherence between the aromatic proton sites H(5) and H(2). The intramolecular distance, however, is by far too large to excite a DQ coherence between these two sites, providing direct evidence for a molecular packing with close proximities between aromatic moieties of neighboring molecules. This kind of interactions is a key element of the complex molecular organization in CIP-SAC (II). Figure 2 (b) shows the 1H-1H DQ NMR correlation spectrum of CIP. A strong autocorrelation signal is present DQ= 3.3 + 3.3 = 6.6 ppm between piperazine protons, allowing the assignment of these proton sites. The cyclopropyl proton sites are well resolved and show correlation signals with protons of the aromatic groups. The 1H-1H DQ MAS spectrum of CIP-SAC (I) (Figure 2 (c)) shows multiplicity of sites. In spite of the complexity, the DQ correlation pattern of CIP-SAC (I) yields features of both, the CIP-SAC (II) DQ correlation spectrum as well as the CIP DQ correlation spectrum . To conclude, CIP-SAC (I) and CIP-SAC (II) exhibit similarities in the molecular conformation. The unknown crystal packing of CIP-SAC (I) presents a molecular site with a packing similar to CIP-SAC (II) and a site with an arrangement closer to that in the pure drug.