Preparation of Chloramphenicol/Amino Acid Combinations Exhibiting Enhanced Dissolution Rates and Reduced Drug-Induced Oxidative Stress.

Chloramphenicol is an old antibiotic agent that is re-emerging as a valuable alternative for the treatment of multidrug-resistant pathogens. However, it exhibits suboptimal biopharmaceutical properties and toxicity profiles. In this work, chloramphenicol was combined with essential amino acids (arginine, cysteine, glycine, and leucine) with the aim of improving its dissolution rate and reduce its toxicity towards leukocytes. The chloramphenicol/amino acid solid samples were prepared by freeze-drying method and characterized in the solid state by using Fourier transform infrared spectroscopy, powder X-ray diffraction, differential scanning calorimetry, scanning electron microscopy, and solid-state nuclear magnetic resonance. The dissolution properties, antimicrobial activity, reactive oxygen species production, and stability of the different samples were studied. The dissolution rate of all combinations was significantly increased in comparison to that of the pure active pharmaceutical ingredient. Additionally, oxidative stress production in human leukocytes caused by chloramphenicol was decreased in the chloramphenicol/amino acid combinations, while the antimicrobial activity of the antibiotic was maintained. The CAP:Leu binary combination resulted in the most outstanding solid system makes it suitable candidate for the development of pharmaceutical formulations of this antimicrobial agent with an improved safety profile.

Paramagnetic solid-state NMR assignment and novel chemical conversion of the aldehyde group to dihydrogen ortho ester and hemiacetal moieties in copper(ii)- and cobalt(ii)-pyridinecarboxaldehyde complexes.

The complex chemical functionalization of aldehyde moieties in Cu(ii)- and Co(ii)-pyridinecarboxaldehyde complexes was studied. X-ray studies demonstrated that the aldehyde group (RCHO) of the four pyridine molecules is converted to dihydrogen ortho ester (RC(OCH3)(OH)2) and hemiacetal (RCH(OH)(OCH3)) moieties in both 4-pyridinecarboxaldehyde copper and cobalt complexes. In contrast, the aldehyde group is retained when the 3-pyridinecarboxaldehyde ligand is complexed with cobalt. In the different copper complexes, similar paramagnetic 1H resonance lines were obtained in the solid state; however, the connectivity with the carbon structure and the 1H vicinities were done with 2D 1H-13C HETCOR, 1H-1H SQ/DQ and proton spin diffusion (PSD) experiments. The strong paramagnetic effect exerted by the cobalt center prevented the observation of 13C NMR signals and chemical information could only be obtained from X-ray experiments. 2D PSD experiments in the solid state were useful for the proton assignments in both Cu(ii) complexes. The combination of X-ray crystallography experiments with DFT calculations together with the experimental results obtained from EPR and solid-state NMR allowed the assignment of NMR signals in pyridinecarboxaldehyde ligands coordinated with copper ions. In cases where the crystallographic information was not available, as in the case of the 3-pyridinecarboxaldehyde Cu(ii) complex, the combination of these techniques allowed not only the assignment of NMR signals but also the study of the functionalization of the substituent group.

Studies of pilocarpine:carbomer intermolecular interactions.

The interactions between pilocarpine (PIL) and the anionic polyelectrolyte carbomer (CBR) were investigated. The effects of the chemical interactions on the chemical stability of the drug also were evaluated. The binary system was characterized by nuclear magnetic resonance techniques, Fourier-transform infrared spectroscopy (FT-IR), X-ray powder diffraction, scanning electron microscopy (SEM) and thermal analysis. The experiments showed that the complex, prepared by freeze-drying, is a solid amorphous form different from its precursors, thereby offering an interesting alternative for the preparation of extended release matrices. The solution stability of PIL was studied at pH 7 and 8, at 70 °C. The PIL solution stability was evaluated alone and in the presence of CBR. Results indicated that the drug in the presence of the polymer is 3.3 and 3.5 times more stable, at pH 7 and pH 8, respectively, than the drug without CBR. The activation energy and the frequency factor, according to Arrhenius plot, were estimated to be 13.9 ± 0.4 and 14.8 ± 0.5 kcalmol(-1), and 6.1 ± 0.3 and 7.6 ± 0.3, with and without the polymer, respectively.

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.

NMR and IR characterization of the aluminium complexes of norfloxacin and ciprofloxacin fluoroquinolones.

A set of new aluminium complexes of norfloxacin (NOR) and ciprofloxacin (CIP) that show an improvement in their pharmaceutical properties were studied using solution and solid-state nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy. The complexes synthesized with two different methods were compared. One of these methods will allow formulation of the compounds at production scale. High-resolution (13)C spectra were obtained with the cross-polarization and magic angle spinning (CP-MAS) experiment. These spectra were assigned by comparing them with the solution data of the pure drug and by using a quaternary carbon edition technique. The carbon relaxation times in the rotating frame, T(1rhoC), were measured for all the complexes. A two-exponential decay evidences that the complexes are nonhomogeneous. The short T(1rhoC) values are in the range 320-1100 micros and the long values in the range 1.8-7 ms. (27)Al MAS NMR spectra revealed an octahedral coordination between the aluminium ion and oxygens of the pure drug, supporting a 3:1 ligand:metal stoichiometry in both CIP and NOR complexes. The stretching and deformation modes of carboxylic acid and carboxylate and keto groups were analyzed by IR. This technique shows that the same modes are present in the aluminium complexes obtained by the two methods and that the coordination of the fluoroquinolone to aluminium occurs through the 4-keto and 3-carboxylic groups.