Assessment of Directional-Hemispherical Reflectance of Tablets with Cefuroxime during Storage under Elevated Temperature and Ultraviolet Radiation.

Environmental conditions can lead to changes in the physical and chemical structures of drug products. In this study, the stability of cefuroxime tablets stored under adverse conditions was evaluated based on total directional-hemispherical reflectance (THR). The THR value was measured before and after the tablets' exposure to stress factors (temperature of 45 °C and UV radiation). Each measurement was performed three times within seven spectral bands at the beginning of the experiment (day 0), and then on days 1, 2, 3, 5, and 7. In addition, hyperspectral profiles (400-1030 nm) were analyzed on days 0 and 7. A significant decrease in THR values in all wavelength ranges was observed when day 7 vs. day 0 were compared, especially for spectral bands of 335-380 nm and 1700-2500 nm (Δ = 0.220, p < 0.001 and Δ = 0.171, p < 0.001, respectively). The hyperspectral analysis confirmed a decrease in the reflectance after the end of stress conditions in the visible light range (400-700 nm) compared to tablets before the experiment. This may indicate that more radiation entered the tablets. In conclusion, the THR of cefuroxime tablets decreases during the exposure to heat and UV radiation, which may result from some physicochemical changes that have occurred during storage.

A fast, cost-saving and sensitive method for determination of cefuroxime in plasma by HPLC with ultraviolet detection.

Cefuroxime (CFX) is a broad-spectrum second-generation cephalosporin and one of the best choices for antibiotic prophylaxis. However, when used in critically ill patients, it may present changes in its pharmacokinetic properties. Therefore, therapeutic drug monitoring of CFX is necessary for effective dosing strategies. A simple, rapid and sensitive liquid chromatographic method with UV detection was developed and validated for the quantification of CFX in plasma. The method involved a single-step precipitation of proteins with methanol and trifluoroacetic acid. Cefuroxime was analyzed on a Brisa LC2 C18 column in isocratic mode consisting of 0.1% trifluoroacetic acid in water and acetonitrile (75:25) with UV detection at a wavelength of 280 nm. The retention times of CFX and cephazolin (internal standard) were 9.8 and 7.4 min, respectively. The calibration curve was linear over a concentration range of 0.25-50 µg/ml. The limits of detection and quantification were 0.1 µg/ml and 0.25 µg/ml, respectively. The accuracy and precision were always <10%. The mean recovery was 93.52%. This fast and simple method could be applied in routine analysis and pharmacokinetic studies.

Molecular Structure of Cefuroxime Axetil Complexes with α-, ß-, γ-, and 2-Hydroxypropyl-ß-Cyclodextrins: Molecular Simulations and Raman Spectroscopic and Imaging Studies.

The formation of cefuroxime axetil+cyclodextrin (CA+CD) complexes increases the aqueous solubility of CA, improves its physico-chemical properties, and facilitates a biomembrane-mediated drug delivery process. In CD-based tablet formulations, it is crucial to investigate the molecular details of complexes in final pharmaceutical preparation. In this study, Raman spectroscopy and mapping were applied for the detection and identification of chemical groups involved in α-, ß-, γ-, and 2-hydroxypropyl-ß-CD (2-HP- ß-CD)+CA complexation process. The experimental studies have been complemented by molecular dynamics-based investigations, providing additional molecular details of CA+CD interactions. It has been demonstrated that CA forms the guest-host type inclusion complexes with all studied CDs; however, the nature of the interactions is slightly different. It seems that both α- and ß-CD interact with furanyl and methoxy moieties of CA, γ-CD forms a more diverse pattern of interactions with CA, which are not observed in other CDs, whereas 2HP-ß-CD binds CA with the contribution of hydrogen bonding. Apart from supporting this interpretation of the experimental data, molecular dynamics simulations allowed for ordering the CA+CD binding affinities. The obtained results proved that the molecular details of the host-guest complexation can be successfully predicted from the combination of Raman spectroscopy and molecular modeling.

Well-Orientation Strategy Biosynthesis of Cefuroxime-Silver Nanoantibiotic for Reinforced Biodentine™ and Its Dental Application against Streptococcus mutans.

Dental caries results from the bacterial pathogen Streptococcus mutans (S. mutans) and is the maximum critical reason for caries formation. Consequently, the present study aims to evaluate the antibacterial activity of a newly synthesized nanoantibiotic-Biodentine formulation. The silver nanoparticles (ROE-AgNPs) were biosynthesized from the usage of Rosmarinus officinalis L. extract (ROE) and conjugated with cefuroxime to form Cefuroxime-ROE-AgNPs. Using Biodentine™ (BIOD), five groups of dental materials were prepared, in which Group A included conventional BIOD, Group B included BIOD with ROE-AgNPs, Groups C and D included BIOD with Cefuroxime-ROE-AgNPs at concentrations of 0.5% and 1.5% cefuroxime, respectively, and Group E included BIOD with 1.5% cefuroxime. The synthesized ROE-AgNPs or Cefuroxime-ROE-AgNPs were characterized for conjugating efficiency, morphology, particle size, and in vitro release. Minimum inhibitory concentration (MIC) of the cefuroxime, ROE-AgNPs, and Cefuroxime-ROE-AgNPs were additionally evaluated against cefuroxime resistant S. mutans, which furthered antibacterial efficacy of the five groups of dental materials. The UV-Visible spectrum showed the ROE-AgNPs or Cefuroxime-ROE-AgNPs peaks and their formation displayed through transmission electron microscopy (TEM), X-ray diffraction (XRD) pattern, and Fourier transforms infrared (FTIR) analysis. The end result of Cefuroxime-ROE-AgNPs showed conjugating efficiency up to 79%. Cefuroxime-ROE-AgNPs displayed the highest antibacterial efficacy against S. mutans as compared to cefuroxime or ROE-AgNPs alone. Moreover, the MIC of ROE-AgNPs and Cefuroxime-ROE-AgNPs was detected against S. mutans to be 25 and 8.5 µg/mL, respectively. Consequently, Cefuroxime-ROE-AgNPs displayed that a decrease in the MIC reached to more than three-fold less than MIC of ROE-AgNPs on the tested strain. Moreover, Cefuroxime-ROE-AgNPs/BIOD was employed as a novel dental material that showed maximum antimicrobial activity. Groups C and D of novel materials showed inhibitory zones of 19 and 26 mm, respectively, against S. mutans and showed high antimicrobial rates of 85.78% and 91.17%, respectively. These data reinforce the utility of conjugating cefuroxime with ROE-AgNPs to retrieve its efficiency against resistant S. mutant. Moreover, the nanoantibiotic delivered an advantageous antibacterial effect to BIOD, and this may open the door for future conjugation therapy of dental materials against bacteria that cause dental caries.

Fabrication and antibacterial properties of cefuroxime-loaded TiO2 nanotubes.

The anodized titanium nanotubes (TiO2-NTs) are considered to be a potential material in clinical therapy. To enhance the antibacterial property of TiO2-NTs, cefuroxime is introduced into TiO2-NTs, and then, different chitosan layers are coated to control the release of cefuroxime. SEM and FTIR are adapted for the characterization of prepared TiO2-NTs. The effects of chitosan coating thickness on release of cefuroxime are also investigated, followed with the antibacterial property evaluation. The results show TiO2-NTs are fabricated by anodization method and cefuroxime is also successfully loaded into the nanotubes. The thickness of chitosan coating is an important factor to the release rate of cefuroxime. Antimicrobial detection and morphology observation of S. aureus show a sustained 7-day drug release and strong negative effect on bacteria. The approach in this study provides a broadly applicable method to fabricate titanium-based orthopedic implants with enhanced antibacterial properties.

Co-processing of cefuroxime axetil by spray drying technique for improving compressibility and flow property.

The aim of the present investigation was to improve the compressibility and flow property of cefuroxime axetil by co-processing it with mannitol and chitosan chlorhydrate using spray drying method. 32 full factorial design, having inlet air temperature and mannitol: chitosan chlorhydrate ratio as independent variables was used for the optimization. Statistical analysis of obtained results revealed that both independent variables had significant effect on response variables (p value < .05). Evaluation of dependent variables suggested, excellent to good flow properties (angle of repose, Carr's index, and Hausner's ratio) for all prepared batches. Desirability function was used for the selection of the optimized batch which was evaluated for Kawakita's equation, Heckel's plot to assess compression behavior of co-processed product under applied pressure. Result of this analysis revealed that the optimized batch product had better compressibility than physical mixture. The tablets prepared by directly compressing spray-dried product, exhibited excellent tensile strength acceptable friability (<1%) and similar release profile when compared with marketed formulation (Similarity factor 89.24 and dissimilarity factor 1.79). So the results of the present investigation concluded that cefuroxime axetil was successfully co-processed with above mentioned excipients by using spray drying method to make it directly compressible.

Surface Dissolution UV Imaging for Investigation of Dissolution of Poorly Soluble Drugs and Their Amorphous Formulation.

The aim of this study is to investigate the dissolution properties of poorly soluble drugs from their pure form and their amorphous formulation under physiological relevant conditions for oral administration based on surface dissolution ultraviolet (UV) imaging. Dissolution of two poorly soluble drugs (cefuroxime axetil and itraconazole) and their amorphous formulations (Zinnat® and Sporanox®) was studied with the Sirius Surface Dissolution Imager (SDI). Media simulating the fasted state conditions (compendial and biorelevant) with sequential media/flow rate change were used. The dissolution mechanism of cefuroxime axetil in simulated gastric fluid (SGF), fasted state simulated gastric fluid (FaSSGF) and simulated intestinal fluid (SIF) is predominantly swelling as opposed to the convective flow in fasted state simulated intestinal fluid (FaSSIF-V1), attributed to the effect of mixed micelles. For the itraconazole compact in biorelevant media, a clear upward diffusion of the dissolved itraconazole into the bulk buffer solution is observed. Dissolution of itraconazole from the Sporanox® compact is affected by the polyethylene glycol (PEG) gelling layer and hydroxypropyl methylcellulose (HPMC) matrix, and a steady diffusional dissolution pattern is revealed. A visual representation and a quantitative assessment of dissolution properties of poorly soluble compounds and their amorphous formulation can be obtained with the use of surface dissolution imaging under in vivo relevant conditions.

Experimental Determination and Theoretical Calculation of the Eutectic Composition of Cefuroxime Axetil Diastereomers.

Cefuroxime axetil (CFA), an ester prodrug of cefuroxime exists as a pair of diastereoemers, namely isomer A and isomer B. To enable phase diagram construction, crystallization of the diastereomers of CFA from the commercially available amorphous drug substance was carried out. Isomer A was separated with a purity approaching 100% whereas the maximum purity of isomer B was 85% as confirmed by solution state proton NMR spectroscopy. The crystalline forms of isomer A and isomer B were confirmed as forms AI and BI, respectively, based on differential scanning calorimetry (DSC) analysis and powder X-ray diffraction. DSC analysis was used to observe the melting behavior of different diastereomer mixture compositions. The binary solid-liquid phase diagram for mixture compositions ranging from 0 to 85% w/w isomer B indicated the formation of a eutectic mixture having a melting temperature of 124.7 ± 0.4°C and a composition of 75% w/w (+/-5% wt.) isomer B. The eutectic composition was calculated using an index based on the van't Hoff equation for melting point depression and was found to be 75% isomer B and 25% isomer A. As CFA is present in commercial preparations as a mixture of diastereomers, the formation of a eutectic mixture between the diastereomers may impact the solubility and stability of the commercial product. Eutectic formation can be explained on the basis of the chemical similarity of diastereomers that favor miscibility in the liquid state.

Stability of 10 mg/mL cefuroxime solution for intracameral injection in commonly used polypropylene syringes and new ready-to-use cyclic olefin copolymer sterile vials using the LC-UV stability-indicating method.

CONTEXT: Injecting intracameral cefuroxime has been found beneficial in reducing the risk of postoperative endophthalmitis but its use has been limited through a lack of approved marketing and of ready-to-use single-units as well as the problem of aseptic compounding. OBJECTIVE: Our aim was to assess a new automated primary packaging system which should ensure a higher level of sterility, thanks to its closed, sterile, ready-to-use polymer vial called "Crystal® vial". The chemical stability of a 10 mg/mL cefuroxime solution was compared in 1 mL Crystal® vials and 1 mL Luer-lock polypropylene syringes (actual reference) to eliminate any potential and specific interactions with its cyclic olefin copolymer (COC) body and elastomer stopper. METHODS: Cefuroxime solution was introduced into vials and syringes and stored at -20 °C, +5 °C and +25°C/60% Relative Humidity. Cefuroxime concentration and the relative amount of the main degradation product (descarbamoyl-cefuroxime) were both determined by an HPLC/UV method indicating stability. Solutions were considered steady if the concentration remained at over 90% of the initial value. In the adapted storage conditions, the evolution of osmolality, pH and sterility was assessed. RESULTS: Stability profiles were identical between vials and syringes in all storage and temperature conditions. The solution was stable (cefuroxime concentration, pH and osmolality) and still sterile for 365 days at -20°C. The concentration fell below 90% after 21 days at +5 °C and after 16 h at +25°C/60%s relative humidity. CONCLUSIONS: The COC and thermoplastic elastomer of the vials had no impact on the degradation process confirming its possible use for a ready-to-use cefuroxime solution single-unit dose.

QbD-Oriented Development and Characterization of Effervescent Floating-Bioadhesive Tablets of Cefuroxime Axetil.

The objective of the present studies was systematic development of floating-bioadhesive gastroretentive tablets of cefuroxime axetil employing rational blend of hydrophilic polymers for attaining controlled release drug delivery. As per the QbD-based approach, the patient-centric target product profile and quality attributes of tablet were earmarked, and preliminary studies were conducted for screening the suitability of type of polymers, polymer ratio, granulation technique, and granulation time for formulation of tablets. A face-centered cubic design (FCCD) was employed for optimization of the critical material attributes, i.e., concentration of release controlling polymers, PEO 303 and HPMC K100 LV CR, and evaluating in vitro buoyancy, drug release, and ex vivo mucoadhesion strength. The optimized formulation was embarked upon through numerical optimization, which yield excellent floatation characteristic with drug release control (i.e., T 60% > 6 h) and bioadhesion strength. Drug-excipient compatibility studies through FTIR and P-XRD revealed the absence of any interaction between the drug and polymers. In vivo evaluation of the gastroretentive characteristics through X-ray imaging and in vivo pharmacokinetic studies in rabbits revealed significant extension in the rate of drug absorption (i.e., T max, K a, and MRT) from the optimized tablet formulation as compared to the marketed formulation. Successful establishment of various levels of in vitro/in vivo correlations (IVIVC) substantiated high degree of prognostic ability of in vitro dissolution conditions in predicting the in vivo performance. In a nutshell, the studies demonstrate successful development of the once-a-day gastroretentive formulations of cefuroxime axetil with controlled drug release profile and improved compliance.

STUDIES OF THE CRYSTALLINE FORM OF CEFUROXIME AXETIL: IMPLICATIONS FOR ITS COMPATIBILITY WITH EXCIPIENTS.

Amorphous and crystalline forms of cefuroxime axetil were identified and characterized using DSC, XRPD, SEM, FT-IR and Raman spectroscopy. Based on the results of chromatographic studies, changes in the kinetic mechanism and rate of degradation of the crystalline form of cefuroxime axetil in binary systems with excipients were also evaluated. The findings suggest that the mechanism of degradation of cefuroxime axetil in such systems depends on two factors: the applied excipient and storage conditions. Cefuroxime axetil in combination with magnesium stearate, croscarmellose sodium and crospovidone, microcrystalline cellulose, aerosil is decomposed according to the first-order reaction model in dry air as well as at an increased relative air humidity, which may be associated with non-catalytic interactions between the active pharmaceutical ingredient and the excipients. However, in the presence of mannitol, under elevated humidity conditions (RH - 76%), the degradation of cefuroxime axetil follows the autocatalytic model. According to ESP maps, computed binding energies and HOMO - LUMO gaps, differences of degradation curves between cefuroxime axetil - mannitol and other investigated systems were explained. This study of the polymorphic transformation of the crystalline form of cefuroxime axetil and its binary systems with excipients after exposure to increased temperature and humidity indicated a conversion towards the amorphous form or the coexistence of both forms.

Application of vibrational spectroscopy supported by theoretical calculations in identification of amorphous and crystalline forms of cefuroxime axetil.

FT-IR and Raman scattering spectra of cefuroxime axetil were proposed for identification studies of its crystalline and amorphous forms. An analysis of experimental spectra was supported by quantum-chemical calculations performed with the use of B3LYP functional and 6-31G(d,p) as a basis set. The geometric structure of a cefuroxime axetil molecule, HOMO and LUMO orbitals, and molecular electrostatic potential were also determined by using DFT (density functional theory). The benefits of applying FT-IR and Raman scattering spectroscopy for characterization of drug subjected to degradation were discussed.

Differentiating amorphous mixtures of cefuroxime axetil and copovidone by X-ray diffraction and differential scanning calorimetry.

The amorphous, molecular solid dispersion of cefuroxime axetil and copovidone with the mass ratio 71/29 is compared to its pure components in the amorphous state and to an amorphous mechanical mixture with the same mass ratio. Calorimetric studies demonstrate that all these materials are vitreous. By using X-ray diffraction profiles, a clear difference can be observed between the local order of the solid dispersion and that of the mechanical mixture. More generally, it is shown how the presence or absence of additivity in the diffraction data can be used to distinguish between different amorphous mixtures.

Halloysite nanotubes-based hybrid silica monolithic spin tip for hydrophilic solid-phase extraction of sulbactam, cefoperazone, and cefuroxime in whole blood.

In this study, we proposed a novel method utilizing polyethyleneimine (PEI)-modified halloysite nanotubes (HNTs)-based hybrid silica monolithic spin tip to analyze hydrophilic ß-lactam antibiotics and ß-lactamases inhibitors in whole blood samples for the first time. HNTs were incorporated directly into the hybrid silica monolith via a sol-gel method, which improved the hydrophilicity of the matrix. The as-prepared monolith was further modified with PEI by glutaraldehyde coupling reaction. It was found that the PEI-modified HNTs-based hybrid silica monolith enabled a large adsorption capacity of cefoperazone at 35.7 mg g-1. The monolithic spin tip-based purification method greatly reduced the matrix effect of whole blood samples and had a detection limit as low as 0.1 - 0.2 ng mL-1. In addition, the spiked recoveries of sulbactam, cefuroxime, and cefoperazone in blank whole blood were in the range of 89.3-105.4 % for intra-day and 90.6-103.5 % for inter-day, with low relative standard deviations of 1.3-7.2 % and 4.9-10.5 %, respectively. This study introduces a new strategy for preparing nanoparticles incorporated in a hybrid silica monolith with a high adsorption capacity. Moreover, it offers a valuable tool to monitor sulbactam, cefoperazone, and cefuroxime in whole blood from pregnant women with the final aim of guiding their administration.

Suspensions of antibiotics in self-emulsifying oils as a novel approach to formulate eye drops with substances which undergo hydrolysis in aqueous environment.

The aim of this study was to develop eye-drops with cefuroxime (CEF) sodium or vancomycin (VAN) hydrochloride, antibiotics that are instable in water. Anhydrous self-emulsifying oils (SEO) are proposed as a carrier and antibiotics are suspended. In the contact with tear fluid, the formulation should transform into emulsion, with fast dissolution of an antibiotic. CEF or VAN (5% w/w) was suspended in SEO carriers prepared by dissolving surfactants (Tween 20 or Span 80 5% w/w) in Miglyol, castor oil, or olive oil. Formulations with or without sodium citrate (2% w/w) were compared. Six-months or 1-year stability tests were carried out at 40 °C. The content of CEF and VAN was evaluated using HPLC and the potency of the antibiotic was assessed with agar diffusion method. In contact with water, drug particles suspended in SEO dissolved rapidly and o/w emulsion was formed. After 1-year at 40 °C, the content of degradation products was at most 0.5% in CEF and 4.0% in VAN formulations. The agar diffusion assay has shown that CEF and VAN loaded into SEO retained its potency against the sensitive microorganisms comparable to an aqueous solution. Therefore, SEO can be used as a novel carrier for the active substances which may not require improved solubility or absorption but need to be protected from moisture. This is a formulation that can be produced on industrial scale, with no limitation of stability or drug concentration.

In vitro/in vivo comparison of cefuroxime release from poly(ε-caprolactone)-calcium sulfate implants for osteomyelitis treatment.

This study aimed to investigate the release of cefuroxime axetil (CF) and calcium from poly(ε-caprolactone) (PCL)-calcium sulfate (CaS) implants (PCL:CaS 2:1-10% CF; PCL:CaS 2:1-20% CF; PCL:CaS 1:1-10% CF) for treating infectious bone diseases. Bioactivity, crystallinity and strength, and release profiles under standard and pressurized release conditions were studied. PCL:CaS 2:1-20% CF had slower release than 10% loading. These groups had no significant change in CF and Ca release in response to pressure. The PCL:CaS 1:1 group had the slowest release despite having higher CaS, probably due to more compaction of discs. In contrast, pressure caused significant differentiation of CF and Ca(2+) release. The presence of CaS enhanced mechanical properties and bioactivity of discs. SEM and XPS results showed calcium-phosphate containing accumulations on surfaces upon SBF incubation. CF-loaded implants were applied in a rabbit osteomyelitis model. In vivo CF release was enhanced with increased CaS proportions, suggesting that in vivo release conditions are closer to pressurized in vitro conditions. In the control group, there was still some inflammation in the bone and no complete coverage with bone was achieved in the defect site. Discs provided a suitable surface for regeneration of bone. However, bone formation in the PCL:CaS 1:1 disc implanted group was more complete and regular than in the 2:1 group.

Susceptibility of cord blood antioxidant enzymes glutathione reductase, glutathione peroxidase and glutathione S-transferase to different antibiotics: in vitro approach.

Cord blood has numerous facilities for life and used in many different areas. Cord blood contains many different catalytic proteins including antioxidant enzymes. Here we purified human cord blood glutathione reductase (hcbGR), glutathione S-transferase (hcbGST) and human cord blood glutathione peroxidase (hcbGPx) from human cord blood erythrocytes and analyzed the inhibition effects of the antibiotics incorporating cefuroxime, ceftriaxone, ceftizoxime and cefoperazone, on these enzymes. K(I) values for the drugs ranged from 10.42 to 28.72 µM for hcbGR, 32.7 to 244.8 µM for hcbGPx, and 32.39 to 267.3 µM for hcbGST. Cefuroxime caused the highest inhibition on all enzymes with KI values of 10.42, 32.39, 32.7 µM for hcbGR, hcbGST, and hcbGPx, respectively. All drugs displayed non-competitive inhibition regardless of their structures. Since these drugs are often used during pregnancy, identification of possible undesired impacts on various parameters has a great importance for pharmacological and medical applications.

Development of gastroretentive drug delivery system for cefuroxime axetil: in vitro and in vivo evaluation in human volunteers.

The objective of this investigation was to develop the cefuroxime axetil sustained-release floating tablets to prolong the gastric residence time and compare their pharmacokinetic behavior with marketed conventional tablets (Zocef). The floating tablets were developed using polymers like HPMC K4M and HPMC K100M alone, and polymer combination of HPMC K4M and Polyox WSR 303 by effervescent technique. Tablets were prepared by slugging method and evaluated for their physical characteristics, in vitro drug release, and buoyancy lag time. The best formulation (F10) was selected based on in vitro characteristics and used in vivo radiographic and bioavailability studies in healthy human volunteers. All the formulations could sustain drug release for 12 h. The dissolution profiles were subjected to various kinetic release models and it was found that the mechanism of drug release followed Peppas model. The in vivo radiographic studies revealed that the tablets remained in stomach for 225 ± 30 min. Based on in vivo performance, the developed floating tablets showed superior bioavailability than Zocef tablet. Based on in vivo performance significant difference was observed between Cmax, tmax, t1/2, AUC0-∞, and mean residence time of test and reference (p<0.05). The increase in relative bioavailability of test was 1.61 fold when compared to reference.

Chitosan-based intragastric delivery of cefuroxime axetil: development and in-vitro evaluation of mucoadhesive approach.

To have advantages of reduced dosing frequency, improved bioavailability and effective delivery system of Cefuroxime Axetil, a Chitosan based intragastric sustained release microbead formulation of Cefuroxime Axetil was developed. The drug delivery system was prepared by ionotropic gelation of Chitosan in presence of sodium tripolyphosphate as polyanion and optimized by box-behnken experimental design. Response surface methodology was applied to evaluate various vitro characteristics of prepared mucoadhesive microbeads. Multiple independent variables were optimized to achieve responses of interest, thereby to get the desired sustained release profile of Cefuroxime Axetil in gastric environment.