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.

Improving Properties of Albendazole Desmotropes by Supramolecular Systems with Maltodextrin and Glutamic Acid.

Albendazole, an effective broad-spectrum anthelmintic agent, showed unpredictable therapeutic response caused by poor water solubility and slow dissolution rate. Then, novel binary and multicomponent supramolecular systems of two different solid forms of albendazole (I and II) with maltodextrin alone or with glutamic acid were studied as an alternative to improve the oral bioavailability of albendazole. The interactions and effects on the properties of albendazole were studied in solution and solid state. The solid systems were characterized using Raman and Fourier transform-infrared spectroscopy, thermal analysis, powder X-ray diffraction, and scanning electron microscopy. The solubility measurements, performed in aqueous and simulated gastric fluid, showed that albendazole (form II) was the most soluble form, while its supramolecular systems showed the highest solubility in simulated gastric fluid. On the other hand, the dissolution profiles of binary and multicomponent systems in simulated gastric fluid displayed pronounced increments of the dissolved drug and a faster dissolution rate compared to those of free albendazole forms. Thus, these supramolecular structures constitute an interesting alternative to improve the physicochemical properties of albendazole, with potential application for the preparation of pharmaceutical oral formulations.

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.

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.

Nanostructured Lipid Carriers as a Strategy to Improve the In Vitro Schistosomiasis Activity of Praziquantel.

Praziquantel (PZQ) is a pyrazinoisoquinoline anthelmintic that was discovered in 1972 by Bayer Germany. Currently, due to its efficacy, PZQ is the drug of choice against all species of Schistosoma. Although widely used, PZQ exhibits low and erratic bioavailability because of its poor water solubility. Nanostructured lipid carriers (NLC), second-generation solid lipid nanoparticles, were developed in the 1990s to improve the bioavailability of poorly water soluble drugs. The aim of this study was to investigate nanostructured lipid carriers as a strategy to improve the efficacy of PZQ in S. mansoni treatment. We prepared NLC2 and NLC4 by adding seventy percent glycerol monostearate (GMS) as the solid lipid, 30% oleic acid (OA) as the liquid lipid and two surfactant systems containing either soybean phosphatidylcholine/poloxamer (PC/P-407) or phosphatidylcholine/Tween 60 (PC/T60), respectively. The carriers were characterized by nuclear magnetic resonance, differential scanning calorimetry, thermogravimetric analysis and Fourier transform-infrared spectroscopy. The safety profile was evaluated using red cell hemolysis and in vitro cytotoxicity assays. The results showed that the encapsulation of PZQ in NLC2 or NLC4 improved the safety profile of the drug. Treatment efficacy was evaluated on the S. mansoni BH strain. PZQ-NLC2 and PZQ-NLC4 demonstrated an improved efficacy in comparison with free PZQ. The results showed that the intestinal transport of free PZQ and PZQ-NLC2 was similar. However, we observed that the concentration of PZQ absorbed was smaller when PZQ was loaded in NLC4. The difference between the amounts of absorbed PZQ could indicate that the presence of T60 in the nanoparticles (NLC4) increased the rigid lipid matrix, prolonging release of the drug. Both systems showed considerable in vitro activity against S. mansoni, suggesting that these systems may be a promising platform for the administration of PZQ for treating schistosomiasis.

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.

Cyclodextrins and Their Derivatives as Drug Stability Modifiers.

Cyclodextrins (CDs) are cyclic oligosaccharides that contain a relatively hydrophobic central cavity and a hydrophilic outer surface. They are widely used to form non-covalent inclusion complexes with many substances. Although such inclusion complexes typically exhibit higher aqueous solubility and chemical stability than pure drugs, it has been shown that CDs can promote the degradation of some drugs. This property of stabilizing certain drugs while destabilizing others can be explained by the type of CD used and the structure of the inclusion complex formed. In addition, the ability to form complexes of CDs can be improved through the addition of suitable auxiliary substances, forming multicomponent complexes. Therefore, it is important to evaluate the effect that binary and multicomponent complexes have on the chemical and physical stability of complexed drugs. The objective of this review is to summarize the studies on the stabilizing and destabilizing effects of complexes with CDs on drugs that exhibit stability problems.

Pharmaceutical Systems as a Strategy to Enhance the Stability of Oxytetracycline Hydrochloride Polymorphs in Solution.

In order to improve the stability of oxytetracycline hydrochloride, a polymorphic antibiotic set of novel binary systems were developed using ß-cyclodextrin and amino acids with different acid-basic characteristics as ligands. The formation constants for each system containing ß-cyclodextrin, L-aspartic acid, histidine and N-acetylcysteine were determined by Scott's method and statistical studies. The structure of the binary systems with ß-cyclodextrin and N-acetylcysteine was elucidated by NMR experiments. The effect ß-cyclodextrin and N-acetylcysteine on the polymorph's chemical stability in aqueous and phosphate buffered saline solutions at 25 °C was monitored by an optimized and validated high-performance liquid chromatography method. The combination of N-acetylcysteine with the three polymorphs and the ß-cyclodextrin system obtained with the form III demonstrated a reduction in the degradation rate of oxytetracycline hydrochloride in the aqueous solution when compared to each free form, with an increase of 20 h in the half time. It evidences that the use of amino acids as ligands constitutes an interesting alternative for pharmaceutical areas. In conclusion, based on the results obtained, these pharmaceutical systems could be candidates for the development of a pharmaceutical formulation for the administration of the drug through reconstituted solutions using the binary system as a promising tool for improving the stability of oxytetracycline hydrochloride polymorphs in solution.

Supramolecular Arrangement of Doxycycline with Sulfobutylether-ß-Cyclodextrin: Impact on Nanostructuration with Chitosan, Drug Degradation and Antimicrobial Potency.

Doxycycline (DX) is a well-established and broad-spectrum antimicrobial drug. However, DX has drawbacks, such as physicochemical instability in aqueous media and bacterial resistance. The inclusion of drugs in cyclodextrin complexes and their loading into nanocarriers can overcome these limitations. Thus, we studied the DX/sulfobutylether-ß-CD (SBE-ß-CD) inclusion complex for the first time and used it to reticulate chitosan. The resulting particles were evaluated by their physicochemical characteristics and antibacterial activity. DX/SBE-ß-CD complexes were characterized by nuclear magnetic resonance, infrared spectroscopy, thermal analysis, X-ray diffraction, and scanning electron microscopy (SEM), whereas DX-loaded nanoparticles were characterized by dynamic light scattering, SEM, and drug content. The partial inclusion of the DX molecule in CD happened in a 1:1 proportion and brought increased stability to solid DX upon thermal degradation. Chitosan-complex nanoparticles measured approximately 200 nm, with a narrow polydispersity and particles with sufficient drug encapsulation for microbiological studies. Both formulations preserved the antimicrobial activity of DX against Staphylococcus aureus, whereas DX/SBE-ß-CD inclusion complexes were also active against Klebsiella pneumoniae, indicating the potential use of these formulations as drug delivery systems to treat local infections.

Amino acids and its pharmaceutical applications: A mini review.

Amino acids are natural compounds that can be safely used in pharmaceutical applications. Considering the great interest in the amino acids used in the pharmaceutical industry, this article presents an overview of investigations reported in recent years. In this regard, the first sections begin with an introductory description of the properties, classification and safety of amino acids, while in the other sections the most common methods for the preparation of amino acids formulations and their application on solubilization, permeation and stabilization of several active pharmaceutical ingredients are described. Furthermore, available data about the multicomponent systems approach is included. Lastly, the impact of amino acids formulations on therapeutic efficacy is explored. The advantages illustrated suggest that amino acids are capable of improving the biopharmaceutical properties of drugs.

Cyclodextrin Multicomponent Complexes: Pharmaceutical Applications.

Cyclodextrins (CDs) are naturally available water-soluble cyclic oligosaccharides widely used as carriers in the pharmaceutical industry for their ability to modulate several properties of drugs through the formation of drug-CD complexes. The addition of an auxiliary substance when forming multicomponent complexes is an adequate strategy to enhance complexation efficiency and to facilitate the therapeutic applicability of different drugs. This review discusses multicomponent complexation using amino acids; organic acids and bases; and water-soluble polymers as auxiliary excipients. Special attention is given to improved properties by including information on the solubility, dissolution, permeation, stability and bioavailability of several relevant drugs. In addition, the use of multicomponent CD complexes to enhance therapeutic drug effects is summarized.

Exploring solid forms of oxytetracycline hydrochloride.

Oxytetracycline hydrochloride, an antibiotic of the tetracycline family, is a polymorphic drug that evidences erratic absorption in oral administration. Additionally, poor solid state characterization of the polymorphs and diversity in the existing nomenclature impede the correct identification of the raw materials. In this work, oxytetracycline hydrochloride solid forms were prepared from isopropyl alcohol, ethanol and methanol through different crystallization techniques, and then their physicochemical and microbiological properties were evaluated. A combination of advanced techniques such as solid state nuclear magnetic resonance, powder X-ray diffraction, infrared spectroscopy, thermal analysis, scanning electron microscopy and energy-dispersive X-ray spectroscopy were used in the characterization of solid samples giving clear evidence of the existence of three stable and one metastable solid forms of the oxytetracycline hydrochloride. Solubility was determined in aqueous solution, simulated gastric fluid, and simulated intestinal fluid. In addition, microbiological studies were performed. The polymorphs showed similar antimicrobial activity against Escherichia coli and Staphylococcus aureus. Therefore, these solid forms of oxytetracycline hydrochloride constitute promising candidates to encourage studies for repositioning old and known antibiotic drugs in the developing strategies for new therapeutic alternatives.

Evaluating ternary systems with oligosaccharides as a strategy to improve the biopharmaceutical properties of furosemide.

Novel ternary systems with ß-cyclodextrin or maltodextrin and triethanolamine as the third component were developed with the aim of improving the oral bioavailability of furosemide. These new solids were characterized by solid-state nuclear magnetic resonance, Fourier transform infrared and Raman spectroscopy, X-ray powder diffractometry, scanning electron microscopy, thermogravimetric analysis, and differential scanning calorimetry. The solubility, dissolution and stability (chemical and physical) were studied. Among the most important results, it was observed that both ternary systems showed an important enhancement in the solubility of the drug. In particular, the system obtained by combination of ß-cyclodextrin and TEA exhibited improvement in the dissolution profiles and photo-stability of furosemide compared with the binary system previously reported. Moreover, this system constitutes an interesting therapeutic alternative as it did not produce cellular toxicity compared with free furosemide. In conclusion, the results obtained revealed that this ternary system establishes a promising approach for oral delivery of the drug.

ß-cyclodextrin complexation as an approach to enhance the biopharmaceutical properties of Norfloxacin B Hydrate.

Binary systems of Norfloxacin B Hydrate with ß-CD were explored by reliable biopharmaceutical studies as potential candidates for the preparation of drug delivery systems. Initially, studies of antimicrobial activity and solubility of the different polymorphic forms of Norfloxacin provided evidence to select Norfloxacin B Hydrate as the optimal solid form of Norfloxacin. Solid binary systems were preparing by kneading, freeze-drying, and physical mixture methods. The influence on the solubility, dissolution rate and chemical stability of Norfloxacin B Hydrate was investigated. These studies showed an increment of solubility and dissolution rate in physiological simulated fluids. However, the solid systems were moderated hygroscopically under accelerated storage conditions, which produces a destabilizing effect that accelerated the chemical reactivity of the drug in such conditions. Therefore, special cares must be considered in the manufacturing process and the packaging selection. Moreover, the experimental results proved that freeze-drying was not an appropriate method for the preparation. In conclusion, the Norfloxacin oral bioavailability can be improved with this binary systems, that could be applied in the production of an alternative pharmaceutical formulation of the drug.

Inclusion complexes of ß-cyclodextrin and polymorphs of mebendazole: Physicochemical characterization.

Mebendazole (MBZ), designated as a WHO essential drug, can exist in diverse solid forms and presents low absorption at the gastrointestinal level. Considering the potential of cyclodextrins to enhance the solubility and permeability of drugs, inclusion complexes of polymorphs A and C of MBZ with ß­cyclodextrin were obtained. The characterization of the complexes in solid state was performed by using a combination of experimental techniques including Fourier transform infrared spectroscopy, powder X-ray diffractometry and solid state nuclear magnetic resonance. Moreover, the effect of the binary complexes on their physical stability was evaluated. In addition, for a complete characterization of polymorphs A and C, one dimensional spectra and correlation nuclear magnetic resonance experiments were employed. Our physical studies showed that the inclusion complexes were new crystalline forms that induced shifts and broadening in the infrared and nuclear spectra. A molecular modelling analysis performed on the inclusion modes, demonstrated that the most favourable structure for the complex was the head down orientation. Moreover, the intermolecular interactions calculated for the complex with the atoms in molecules theory are in good agreement with the spectroscopic results. The inclusion complexes exhibited an increment of solubility in simulated physiological media. Furthermore, it was demonstrated that the complex formation did not affect the physical stability of the polymorphs.

Synthesis, characterization and in vitro release studies of a new acetazolamide-HP-beta-CD-TEA inclusion complex.

The aim of our work was to develop a multicomponent inclusion complex of acetazolamide (ACZ) in order to investigate the combined effect of hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and triethanolamine (TEA) on the solubility of ACZ and its possibility of ophthalmic delivery. Phase solubility study was used to evaluate the complexation in solution at 25 degrees C. Complex formation was also evaluated by comparing the infrared (FT-IR) spectra of the solid complexes with a simple physical mixture containing the same amount of ACZ. FT-IR experiments provided data indicating that the carbonamido group of ACZ is involved in the inclusion process. In vitro release data showed that both formulations, containing the freeze-dried ternary complex and the corresponding simple physical mixture of ACZ with HP-beta-CD and TEA presented the fastest release rate of ACZ. These results suggest that the ACZ-HP-beta-CD-TEA complex represents an effective novel formulation to enhance ACZ solubility in water, turning it promising for ophthalmic administration.

Binary and ternary complexes of norfloxacin to improve the solubility of the active pharmaceutical ingredient.

AIM: Binary and ternary complexes with hydroxypropyl-ß-cyclodextrin (HPßCD), using glutamic acid (GA), proline or lysine as the third component, were developed to increase the solubility and the dissolution rate of norfloxacin (NOR). METHODS/RESULTS: Complexation was evaluated by phase solubility studies, obtaining the highest NOR solubility with GA and HPßCD. Thermal analysis suggested that different kinds of interactions occur among NOR, HPßCD and each amino acid, and when the systems were prepared by kneading or by means of freeze-drying technique. Dissolution studies, performed on simulated gastric fluid and subsequent simulated intestinal fluid, showed the highest rate of NOR from NOR-HPßCD-GA. CONCLUSION: NOR:HPßCD:GA was the best approach for improving the bioavailability of NOR.

Characterization of systems with amino-acids and oligosaccharides as modifiers of biopharmaceutical properties of furosemide.

Furosemide is the most commonly prescribed diuretic drug in spite of its suboptimal biopharmaceutical properties. In this work, the addition of different amino-acids was studied with the aim of selecting an enhancer of the furosemide solubility. The best results were obtained with arginine. Also, binary (furosemide:arginine) and ternary (furosemide:arginine:ß-cyclodextrin and furosemide:arginine:maltodextrin) systems were prepared by the kneading method and they were compared with their corresponding physical mixtures. These new systems were characterized by Fourier transform infrared and Raman spectroscopy, X-ray powder diffractometry, scanning electron microscopy, thermogravimetric analysis, and differential scanning calorimetry. In addition, dissolution studies were performed in simulated gastric fluid. The best results in relation to improving biopharmaceutical properties were obtained with a binary combination of furosemide and arginine, demonstrating that this system could result in a suitable candidate for the development of a promising pharmaceutical formulation of the drug.

Study of ascorbic acid interaction with hydroxypropyl-beta-cyclodextrin and triethanolamine, separately and in combination.

Complexation between ascorbic acid, hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and triethanolamine (TEA), separately and in combination, was studied in solution and solid state. The freeze-drying method was used to prepare solid complexes, while physical mixtures being obtained by simple blending. These complexes were characterized in the solid state using differential scanning calorimetry (DSC) and infrared spectroscopy (IR). Nuclear magnetic resonance spectroscopy ((1)H and (13)C NMR) was used in aqueous solutions to obtain information about the mode of interaction. The degradation rate of each complex in solution was determined, and the stability constant of the complexes and the degradation rate of the ascorbic acid within the complexes were obtained. NMR studies provided clear evidence of partial inclusion into the HP-beta-CD cavity, but the stability constant value was very small indicating a weak host-guest interaction. The influence of complexation on the degradation rate of ascorbic acid was evaluated, and the data obtained showed a pronounced enhancement of aqueous stability with the TEA association complex, while this effect was lower with the HP-beta-CD inclusion complex. NMR experiments showed evidence of the formation of aggregates.

Toward novel antiparasitic formulations: Complexes of Albendazole desmotropes and ß-cyclodextrin.

Novel complexes of two different solid forms of Albendazol and ß-cyclodextrin were investigated in an attempt to obtain promising candidates for the preparation of alternative matrices used in pharmaceutical oral formulations. The interaction between each form of Albendazol and ß-cyclodextrin was studied in solution and solid state, in order to investigate their effect on the solubility and dissolution rate of Albendazol solid forms. The solid supramolecular systems were characterized using a variety of techniques including natural-abundance 13C cross-polarization magic-angle-spinning nuclear magnetic resonance, powder X-ray diffraction, Fourier transform-infrared spectroscopy and scanning electron microscopy. The results obtained showed the highest increment of solubility and dissolution rate, in simulated gastric fluid, for the Albendazole II:ß-cyclodextrin systems. Thus, these new complexes constitute an interesting alternative for improving the oral bioavailability of Albendazol.