Ana K. Chattah

Characterization of the solubility and solid‐state properties of saccharin salts of fluoroquinolones

Saccharinates salts of the fluoroquinolone antibiotics norfloxacin, ciprofloxacin, ofloxacin, and enrofloxacin were obtained as pure crystalline anhydrous solids with sweet taste. The products were characterized by one- ((13)C) and two-dimensional ((1)H-(13)C) dimensions solid state Nuclear Magnetic Resonance and infrared spectroscopy showing ionic interactions between the saccharine amide and the fluoroquinolone piperazine. Several intermolecular bindings were also identified. Thermal behavior and powder X-ray diffraction provided complementary evidences of salt formation. The series of products showed improved properties with respect to water solubility. A solubility model was developed. These salts would be a good way forward to developing more suitable formulations of these APIs.

Investigating Albendazole Desmotropes by Solid-State NMR Spectroscopy

Characterization of the molecular structure and physicochemical solid-state properties of the solid forms of pharmaceutical compounds is a key requirement for successful commercialization as potential active ingredients in drug products. These properties can ultimately have a critical effect on the solubility and bioavailability of the final drug product. Here, the desmotropy of Albendazole forms I and II was investigated at the atomic level. Ultrafast magic angle spinning (MAS) solid-state nuclear magnetic resonance (NMR) spectroscopy, together with powder X-ray diffraction, thermal analysis, and Fourier transform infrared spectroscopy, were performed on polycrystalline samples of the two solids in order to fully characterize and distinguish the two forms. High-resolution one-dimensional (1)H, (13)C, and (15)N together with two-dimensional (1)H/(1)H single quantum-single quantum, (1)H/(1)H single quantum-double quantum, and (1)H/(13)C chemical shift correlation solid-state NMR experiments under MAS conditions were extensively used to decipher the intramolecular and intermolecular hydrogen bonding interactions present in both solid forms. These experiments enabled the unequivocal identification of the tautomers of each desmotrope. Our results also revealed that both solid forms may be described as dimeric structures, with different intermolecular hydrogen bonds connecting the tautomers in each dimer.

Supramolecular complexes of maltodextrin and furosemide polymorphs: a new approach for delivery systems

We present new supramolecular complexes of two different solid forms of furosemide (I or II) with maltodextrin, in order to explore their application as delivery systems improving the bioavailability of the drug. The complexation in solution was evaluated by (1)H nuclear magnetic resonance experiments and phase solubility studies. The products in solid state were exhaustively characterized by using spectroscopic techniques ((13)C solid state nuclear magnetic resonance, infrared, scanning electron microscopy, X-ray powder diffractometry) and thermal analysis. (1)H relaxation times experiments gave further support in distinguishing the new solid forms. Dissolution studies in simulated gastric fluid showed that both supramolecular complexes presented significant increase in the dissolution, while the corresponding physical mixtures exhibited the most discriminating conditions between the furosemide forms I and II. Our results suggest the enhancement of the solubility and the dissolution of furosemide in the new complexes, making them promising candidates for the preparation of alternative matrices in oral pharmaceutical formulations.

Improving furosemide polymorphs properties through supramolecular complexes of β-cyclodextrin.

In this work, complexes of β-cyclodextrin and the two solid forms of furosemide were prepared and characterized for their potential pharmaceutical applications, with the interactions between the two compounds being studied in the solution and solid states. The solubility studies revealed different behaviors of the polymorphs. In particular, it was observed that the binary complex significantly increased the solubility of furosemide form I in the gastric simulated fluid, which resulted in a rise in the bioavailability of this formulation after oral administration. In addition, results using ssNMR, FT-IR, DSC, TGA, SEM and XRPD provided evidence of the formation of complexes after utilizing kneading and freeze-drying methods. A comparison with previous developed complexes that used maltodextrin as the ligand was performed. Our results suggest that these novel supramolecular complexes showed promise to be used in drug delivery systems with an application in pharmaceutical formulations.

Crystallographic, thermal and spectroscopic characterization of a ciprofloxacin saccharinate polymorph.

A new polymorphic form of ciprofloxacin saccharinate (CIP-SAC II) is presented, and compared with CIP-SAC I, a different polymorph which we had previously reported. The characterization techniques used were single crystal and powder X-ray diffraction, differential scanning calorimetry, thermogravimetry analysis and infrared and (13)C solid-state nuclear magnetic resonance spectroscopy. The results obtained from these techniques are consistent. Differential scanning calorimetry and thermogravimetric analysis showed that the reaction between the precursors is completed and the crystalline forms of both salts obtained (I and II) are highly pure. Infrared spectroscopy gave clear evidence of a salt formation. Solid-state nuclear magnetic resonance spectroscopy would indicate some degree of qualitative similarity in the intermolecular interaction scheme in both polymorphs, while thermal analysis data might indicate a difference in quantitative terms. A thorough single crystal structure determination of the new form CIP-SAC II allowed disclosing the most important inter- and intramolecular interactions.

Insights into Novel Supramolecular Complexes of Two Solid Forms of Norfloxacin and β-Cyclodextrin

The solid-state properties of novel complexes of β-cyclodextrin and two different solid forms of norfloxacin were investigated at the molecular level, in an attempt to obtain promising candidates for the preparation of alternative matrices used in pharmaceutical oral formulations. In order to evaluate the physical properties inherited from the different polymorphs, these supramolecular systems were characterized using a variety of spectroscopic techniques including natural-abundance (13) C cross-polarization magic-angle-spinning (CP-MAS) nuclear magnetic resonance (NMR), powder X-ray diffraction, and Fourier transform infrared spectroscopy. The intrinsic proton spin-lattice relaxation times detected in (13) C CP-MAS NMR spectra are used to confirm and distinguish the complex formation, as well as to provide better insights into the molecular fragments that are involved in the interaction with β-cyclodextrin.

Many-spin quantum dynamics during cross polarization in 8CB

We analyze theoretically and experimentally the quantum dynamics of a three-spin-1/2 system during cross polarization (CP). Our analysis takes into account a Hamiltonian behavior for a carbon 13C coupled to two protons 1H while the coupling to a spin bath is treated in the fast fluctuation approximation. This model is applied to the methylene and biphenyl groups of the smectic and nematic phases of the liquid crystal 4-n-octyl-4′-cyanobiphenyl (8CB). Experimental data from standard CP, combined with our theoretical results, allow us to separate the homonuclear 1H–1H and heteronuclear 1H–13C residual dipolar couplings. These values are in good agreement with those obtained by using a combination of CP under Lee–Goldburg conditions and standard CP data. A well differentiated relaxation behavior among the two phases seems to indicate that while the extreme narrowing approximation is appropriate for the nematic phase, the description of the smectic phase requires consideration of the slow-motion limit.

NMR polarization echoes in a nematic liquid crystal.

We have modified the polarization echo (PE) sequence through the incorporation of Lee-Goldburg cross polarization steps to quench the 1H-1H dipolar dynamics. In this way, the 13C becomes an ideal local probe to inject and detect polarization in the proton system. This improvement made possible the observation of the local polarization P(00)(t) and polarization echoes in the interphenyl proton of the liquid crystal N-(4-methoxybenzylidene)-4-butylaniline. The decay of P(00)(t) was well fitted to an exponential law with a characteristic time tau(C) approximately 310 micros. The hierarchy of the intramolecular dipolar couplings determines a dynamical bottleneck that justifies the use of the Fermi Golden Rule to obtain a spectral density consistent with the structural parameters. The time evolution of P(00)(t) was reversed by the PE sequence generating echoes at the time expected by the scaling of the dipolar Hamiltonian. This indicates that the reversible 1H-1H dipolar interaction is the main contribution to the local polarization decrease and that the exponential decay for P(00)(t) does not imply irreversibility. The attenuation of the echoes follows a Gaussian law with a characteristic time tau(phi) approximately 527 micros. The shape and magnitude of the characteristic time of the PE decay suggest that it is dominated by the unperturbed homonuclear dipolar Hamiltonian. This means that tau(phi) is an intrinsic property of the dipolar coupled network and not of other degrees of freedom. In this case, one cannot unambiguously identify the mechanism that produces the decoherence of the dipolar order. This is because even weak interactions are able to break the fragile multiple coherences originated on the dipolar evolution, hindering its reversal. Other schemes to investigate these underlying mechanisms are proposed.

NMR Characterization of Hydrate and Aldehyde Forms of Imidazole-2-carboxaldehyde and Derivatives

The existence and stability of the aldehyde-hydrate form of imidazole-2-carboxaldehyde (4) were studied using FTIR together with solution- and solid-state NMR experiments. The results allowed us to conclude that the hydrate form was stable and precipitated at pH = 8.0 and that the aldehyde form was isolated at pH = 6.5 and 9.5. Moreover, the presence of the aldehyde-hydrate form was studied through NMR experiments in D(2)O at both alkaline and acidic pH. In addition, the tautomeric forms of the 2-substituted imidazole compounds were also analyzed to investigate the influence of the hybridization on the carbon adjacent to the imidazole ring, by (13)C NMR in DMSO-d(6), acetone-d(6), and CDCl(3). The presence of the syn- and anti-isomers of oxime 8 obtained from 4 were characterized by solid-state NMR and variable-temperature NMR experiments in acetone-d(6).

Chapter Four – Solid-State Nuclear Magnetic Resonance in Pharmaceutical Compounds

Abstract The solid-state characterization of novel pharmaceutical compounds remains an important issue. Solid-state NMR is one of the techniques of choice to gain information when other techniques are not available. Knowledge of the molecular structure in the solid state can lead to better design and control the behaviour of the drug as it affects important properties such as solubility in aqueous medium. Many different NMR experiments can be performed to obtain either structural or dynamic information on very broad space and time ranges, respectively. Contrary to others techniques, not only crystalline material but also amorphous materials can be studied by SSNMR. These and other aspects make SSNMR a very powerful technique to obtain relevant information on solids pharmaceutical forms. We will discuss the SSNMR most common experiments used to investigate pharmaceutical compounds, including one- and two-dimensional experiments and relaxation time measurements. Additionally, we will mention some aspects of first principle calculation. Also we highlight the importance of NMR as a multinuclear technique. We will focus on SSNMR applied for characterization of new developed active pharmaceutical compounds and formulated drugs. We will pay attention to some particular topics as polymorphism, complexes with cyclodextrin and an emerging issue in pharmaceutical industry as it is the development of cocrystals. NMR crystallography is also discussed.