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

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

Angra dos Reis

Encuentro; 13th Nuclear Magnetic Resonance Users Meeting; 2011

13th Nuclear Magnetic Resonance Users Meeting

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. Figure 1 shows the chemical structure of CIP-SAC and the labels used in this work and the 1H NMR spectra for (a) CIP, (b) CIP-SAC (I) and (c) CIP-SAC (II). In the spectrum of CIP, aromatic protons (H(2), H(5) and H(8)) appear unresolved. Signals from methylene groups (H(1b) and H(1c)) are resolved but are observed at negative ppm. These negative chemical shift values can  be attributed to strong interactions between methylene groups and neighboring aromatic moieties.(6)   In the 1H solid state spectra of CIP-SAC (I) we can observe three signals in the range from 10?15 ppm, two of them correspond to the carboxyl proton, a clear evidence of the existence of at least two molecules in the asymmetric unit in this polymorph.(4) Methylene protons in CIP-SAC (I) are detected at negative ppm values under the presence of ring currents from aromatic moieties in close spatial proximity. CIP-SAC (II) presents fewer resonance than the former sample. No shifts to negative ppm values can be seen in this compound, indicating a substantial difference in the crystal structure compared to the other polymorph. Note that the NH(14)+ signals in the two polymorphs are shifted towards lower frequency values relative to that of CIP. This is indicative of the salt formation. In contrast, because of the zwitterionic character of CIP, on formation of the salt, protons from the piperazine (Pip) group do not exhibit significant changes. The 1H-1H DQ MAS correlation spectrum of CIP-SAC (II) (Figure 2 (a)) shows strong autocorrelation peaks at wDQ= 6.6 ppm and wDQ= 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 wDQ = 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 wDQ= 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.