Improving the Stability and the Pharmaceutical Properties of Norfloxacin Form C Through Binary Complexes with ß-Cyclodextrin.

Norfloxacin, an antibiotic that exists in different solid forms, has very unfavorable properties in terms of solubility and stability. Binary complexes of norfloxacin, in the solid form C, and ß-cyclodextrin were procured by the kneading method and physical mixture. Their effect on the solubility, the dissolution rate, and the chemical and physical stability of norfloxacin was evaluated. To perform stability studies, the solid samples were stored under accelerated storage conditions, for a period of 6 months. Physical stability was monitored through powder X-ray diffraction, high-resolution 13C solid-state nuclear magnetic resonance, and scanning electron microscopy. The results showed evidence that the kneaded complex increased and modulated the dissolution rate of norfloxacin C. Furthermore, it was demonstrated that the photochemical stability was increased in the complex, without affecting its physical stability. The results point to the conclusion that the new kneading complex of norfloxacin constitutes an alternative tool to formulate a potential oral drug delivery system with improve oral bioavailability.

Generation and Stability of the gem-Diol Forms in Imidazole Derivatives Containing Carbonyl Groups. Solid-State NMR and Single-Crystal X-ray Diffraction Studies.

The stability of gem-diol forms in imidazolecarboxaldehyde isomers was studied by solid-state nuclear magnetic resonance (ss-NMR) combined with single-crystal X-ray diffraction studies. These methodologies also allowed determining the factors governing the occurrence of such rare functionalization in carbonyl moieties. Results indicated that the position of the carbonyl group is the main factor that governs the generation of geminal diols, having a clear and direct effect on hydration, since, under the same experimental conditions, only 36% of 5-imidazolecarboxaldehydes and 5% of 4-imidazolecarboxaldehydes were hydrated, as compared to 2-imidazolecarboxaldehydes, with which a 100% hydration was achieved. Not only did trifluoroacetic acid favor the addition of water to the carbonyl group but also it allowed obtaining single crystals. Single crystals of the gem-diol and the hemiacetal forms 2-imidazolecarboxaldehyde and N-methyl-2-imidazolecarboxaldehyde, respectively, were isolated and studied through 1H ss-NMR. Mass spectrometry and solution-state NMR experiments were also performed to study the hydration process.

gem-Diol and Hemiacetal Forms in Formylpyridine and Vitamin-B6-Related Compounds: Solid-State NMR and Single-Crystal X-ray Diffraction Studies.

The gem-diol moieties of organic compounds are rarely isolated or even studied in the solid state. Here, liquid- and solid-state NMR, together with single-crystal X-ray diffraction studies, were used to show different strategies to favor the gem-diol or carbonyl moieties and to isolate hemiacetal structures in formylpyridine and vitamin-B6-related compounds. The change in position of the carbonyl group in pyridine compounds had a clear and direct effect on the hydration, which was enhanced by trifluoroacetic acid addition. Because of their biochemical importance, vitamin-B6-related compounds were studied with emphasis on the elucidation of the gem-diol, cyclic hemiacetal or carbonyl structures that can be obtained in different experimental conditions. In particular, new racemic mixtures for the cyclic hemiacetal structure from pyridoxal are reported in trifluoroacetate and hydrochloride derivatives.

Stability of furosemide polymorphs and the effects of complex formation with ß-cyclodextrin and maltodextrin.

The effect of the formation of supramolecular binary complexes with ß-cyclodextrin and maltodextrin on the chemical and physical stability of the polymorphs I and II of furosemide was evaluated in solid state. The solid samples were placed under accelerated storage conditions and exposed to daylight into a stability chamber for a 6-month. Chemical stability was monitored by high performance liquid chromatography, while the physical stability was studied by solid state nuclear magnetic resonance, powder X-ray diffraction and scanning electron microscopy. Changes in the physical appearance of the samples were evaluated. The studies showed a significant stabilizing effect of ß-cyclodextrin on furosemide form II. Our results suggest that the complex formation is a useful tool for improving the stability of furosemide polymorphs. These new complexes are promising candidates that can be used in the pharmaceutical industry for the preparation of alternative matrices that improve physicochemical properties.

Influence of ß-cyclodextrin on the Properties of Norfloxacin Form A.

Cyclodextrins are able to form host-guest complexes with hydrophobic molecules to result in the formation of inclusion complexes. The complex formation between norfloxacin form A and ß-cyclodextrin was studied by exploring its structure affinity relationship in an aqueous solution and in the solid state. Kneading, freeze-drying, and physical mixture methods were employed to prepare solid complexes of norfloxacin and ß-cyclodextrin. The solubility of norfloxacin significantly increased upon complexation with ß-cyclodextrin as demonstrated by a solubility isotherm of the AL type along with the results of an intrinsic dissolution study. The complexes were also characterized in the solid stated by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier-transform infrared (FT-IR) spectroscopy, X-ray diffractometry, scanning electron microscopy (SEM), and solid-state nuclear magnetic resonance (ssNMR) spectrometry. The thermal analysis showed that the thermal stability of the drug is enhanced in the presence of ß-cyclodextrin. Finally, the microbiological studies showed that the complexes have better potency when compared with pure drug.

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

In this work, complexes of ß-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.

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.

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).

Solution and solid state properties of a set of procaine and procainamide derivatives.

A set of potential Class III antiarrhythmic agents of structure p-HOOC-R-CO-NH-C(6)H(4)-CO-X-C(2)H(5)-N(C(2)H(5))(2) were isolated as crystalline solids of the amide and ester derivatives, I: succinylprocainamide (X=-NH-, R=-C(2)H(4)-); II: succinylprocaine (X=-O-, R=-C(2)H(4)-); III: maleylprocainamide (X=-NH-, R=-C(2)H(2)-) and IV: maleylprocaine (X=-O-, R=-C(2)H(2)-). Although compounds I-IV exhibit similar solution properties (i.e. acid-base speciation, with zwitterionic (+-) to neutral (00) form ratios higher than 10(4)), aqueous solubility of -NH- derivatives is significantly higher than that of -O- derivatives and also, solvent effects on solubility (i.e. the change of water by ethanol) is clearly different in both series. Solution and solid-state properties of I-IV were characterized to account for the observed differences. Results indicate that procainamide derivatives I and III crystallizes as (+-)(s) but procaine derivatives II and IV as (00)(s). Besides, I is anhydrous but II-IV are hydrates. Aqueous solubility and solvent effect on solubility are controlled by the intrinsic solubility of the species (+-) in I and III and (00) in II and IV. The rise of hydrophilicity of species (00) due to the structural change from -O- to -NH- would determine the change in the structure of the precipitating crystals from (00)(s) to (+-)(s). Solid structure (zwitterionic or neutral), as well as composition (anhydrous or hydrated) may be recognized as the main factors in determining the rank of aqueous solubility of the set: (+-)>(+-.H(2)O)>(00.H(2)O).