Magdalena Paczkowska

β-Cyclodextrin complexation as an effective drug delivery system for meropenem.

Following the preparation of an inclusion complex of β-cyclodextrin and meropenem, methods based on FT-IR, Raman and DSC were used for its characterization. An analysis of changes in the stability of meropenem after complexation showed that the complex may serve as a valuable delivery system significantly contributing to enhanced meropenem stability in aqueous solutions and in the solid phase. Due to a sustained transfer of meropenem from the cavity of the cyclodextrin it was possible to maintain a constant desired meropenem concentration over a period of 20 h, as confirmed by a release study. An evaluation of microbial activity not only demonstrated that the bactericidal action of meropenem was not stopped as a result of complexation but even pointed to greater growth inhibition in certain clinically important strains. The fact that investigations of meropenem stability and microbial activity proposed the carbonyl groups as those domains of a meropenem molecule that are instrumental in the formation of a complex with β-cyclodextrin supports the findings of theoretical studies based on molecular modeling.

Solid-state stability study of meropenem – solutions based on spectrophotometric analysis

BackgroundB-Lactam antibiotics are still the most common group of chemotherapeutic drugs that are used in the treatment of bacterial infections. However, due to their chemical instability the potential to apply them as oral pharmacotherapeutics is often limited and so it is vital to employ suitable non-destructive analytical methods. Hence, in order to analyze such labile drugs as β-lactam analogs, the application of rapid and reliable analytical techniques which do not require transferring to solutions or using organic solvents, following the current green approach to pharmaceutical analysis, is necessary. The main objective of the present research was to develop analytical methods for the evaluation of changes in meropenem in the solid state during a stability study.ResultsThe UV, FT-IR and Raman spectra of meropenem were recorded during a solid-state stability study. The optimum molecular geometry, harmonic vibrational frequencies, infrared intensities and Raman scattering activities were calculated according to the density-functional theory (DFT/B3LYP method) with a 6-31G(d,p) basis set. As the differences between the observed and scaled wavenumber values were small, a detailed interpretation of the FT-IR and Raman spectra was possible for non-degraded and degraded samples of meropenem. The problem of the overlapping spectra of meropenem and ring-containing degradation products was solved by measuring changes in the values of the first-derivative amplitudes of the zero-order spectra of aqueous solutions of meropenem. Also, molecular electrostatic potential (MEP), front molecular orbitals (FMOs) and the gap potential between highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) were determined.ConclusionsBased on the findings of this work, it appears possible to use time-saving and reliable spectrophotometric analytical methods, supported by quantum-chemical calculations, for solid-state stability investigations of meropenem. The methods developed for this study may be considered a novel, green solution to pharmaceutical analysis of labile drugs – an alternative for the recommended chromatographic procedures.

Complex of Rutin with β-Cyclodextrin as Potential Delivery System

This study aimed to obtain and characterize an RU-β-CD complex in the context of investigating the possibility of changes in the solubility, stability, antioxidative and microbiological activity as well as permeability of complexated rutin as against its free form. The formation of the RU-β-CD complex via a co-grinding technique was confirmed by using DSC, SEM, FT-IR and Raman spectroscopy, and its geometry was assessed through molecular modeling. It was found that the stability and solubility of the so-obtained complex were greater compared to the free form; however, a slight decrease was observed inits antibacterial potency. An examination of changes in the EPR spectra of thecomplex excluded any reducing effect of complexation on the antioxidative activity of rutin. Considering the prospect of preformulation studies involving RU-β-CD complexes, of significance is also the observed possibility of prolongedly releasing rutin from the complex at a constant level over along period of 20 h, and the fact that twice as much complexated rutin was able topermeate compared to its free form.

Application of spectroscopic methods for identification (FT-IR, Raman spectroscopy) and determination (UV, EPR) of quercetin-3-O-rutinoside. Experimental and DFT based approach.

Vibrational (FT-IR, Raman) and electronic (UV, EPR) spectral measurements were performed for an analysis of rutin (quercetin-3-O-rutinoside) obtained from Rutaofficinalis. The identification of rutin was done with the use of FT-IR and Raman spectra. Those experimental spectra were determined with the support of theoretical calculations based on a DFT method with the B3LYP hybrid functional and 6-31G(d,p) basis set. The application of UV and EPR spectra was found to be a suitable analytical approach to the evaluation of changes in rutin exposed to certain physicochemical factors. Differences in absorbance observed in direct UV spectra were used to monitor changes in the concentration of rutin in degraded samples. Spectra of electron paramagnetic resonance allowed studying the process of free-radical quenching in rutin following its exposure to light. The molecular electrostatic potential (MEP) and frontier molecular orbitals (LUMO-HOMO) were also determined in order to predict structural changes and reactive sites in rutin.

The use of UV, FT-IR and Raman spectra for the identification of the newest penem analogs: Solutions based on mathematic procedure and the density functional theory

The application of ultraviolet, FT-IR and Raman spectra was proposed for identification studies of the newest penem analogs (doripenem, biapenem and faropenem). An identification of the newest penem analogs based on their separation from related substances was achieved after the application of first derivative of direct spectra in ultraviolet which permitted elimination of overlapping effects. A combination of experimental and theoretical studies was performed for analyzing the structure and vibrational spectra (FT-IR and Raman spectra) of doripenem, biapenem and faropenem. The calculations were conducted using the density functional theory with the B3LYP hybrid functional and 6-31G(d,p) basis set. The confirmation of the applicability of the DFT methodology for interpretation of vibrational IR and Raman spectra of the newest penem analogs contributed to determination of changes of vibrations in the area of the most labile bonds. By employing the theoretical approach it was possible to eliminate necessity of using reference standards which - considering the instability of penem analogs - require that correction coefficients are factored in.

Stability, compatibility and microbiological activity studies of meropenem-clavulanate potassium.

Meropenem (MEM) and clavulanate potassium have been reported to demonstrate highly effective activity against Mycobacterium tuberculosis. There have been no reports on research into the complex of these chemotherapeutics concerning their mutually dependent stability or microbiological action on other microorganisms. Stability and compatibility studies of MEM/clavulanate potassium were conducted by using an HPLC-DAD method. The antibacterial activity of MEM/clavulanate potassium was tested in vitro against a selection of indicator bacteria strains by determining the MIC as well as analyzing the kinetics of changes in the concentrations of Pseudomonas aeruginosa, Staphylococcus aureus and Listeria monocytogenes caused by the action of MEM/clavulanate potassium. The stability and compatibility of MEM/clavulanate potassium were examined in aqua pro iniectione, 0.9% NaCl and 5% glucose at room temperature and at 5 °C. The degradation rates of MEM/clavulanate potassium depended on the type of infusion solvent used. Although in aqueous solutions of MEM/clavulanate potassium neither compound showed any mutual impact on the rate of degradation, clavulanate potassium was more labile than MEM. The synergy between these two resulted in a significantly lower value of MIC as compared to the values observed for the individual activity of either compound. The infusion solvent in which compatibility is observed between the components of the mixture MEM/clavulanate potassium is aqua pro iniectione. The complex MEM/clavulanate potassium demonstrates synergic antibacterial activity against P. aeruginosa, S. aureus and L. monocytogenes.

Stability studies of cefoselis sulfate in the solid state

The process of degradation was studied by using an HPLC-DAD method. Two degradation products were identified with a hybrid ESI-Q-TOF mass spectrometer. The influence of temperature and relative air humidity (RH) on the stability of cefoselis sulfate was investigated. In the solid state at increased RH the degradation of cefoselis sulfate was an autocatalytic reaction of the first order with respect to substrate concentration while in dry air was first-order reaction depending on the substrate concentration. The kinetic and thermodynamic parameters of degradation were calculated.

The Chromatographic Approach to Kinetic Studies of Tebipenem Pivoxil

A validated high-performance liquid chromatography-diode array detector (HPLC-DAD) method for stability studies of tebipenem pivoxil was developed. The separation of tebipenem pivoxil in the presence of main degradation product—tebipenem—was achieved by using a LiChrospher C-18 column (5 µm, 250 × 4.6 mm) with the mobile phase containing a mixture of 50 mmol L(-1) ammonium acetate-acetonitrile-triethylamine (68 : 30 : 2, v/v/v) adjusted to pH 3.5 with concentrated phosphoric acid (V). The column effluent was monitored by a photodiode array detector at 330 nm. The flow rate was 0.8 mL min(-1). Tebipenem pivoxil was subjected to degradation in aqueous solutions (acid-base hydrolysis, oxidation) and in the solid state (photolysis, thermolysis at an increased relative humidity and in dry air). The validated HPLC method was successfully applied to investigate the kinetics of conversion of tebipenem pivoxil to tebipenem (main metabolite). The other degradation products of tebipenem pivoxil were also monitored.

Tebipenem pivoxyl. Derivative spectroscopy study of stability of the first oral carbapenem

A simple and selective derivative spectrophotometric method was developed for the quantitative determination of tebipenem and its pivoxyl ester in the presence of degradation products formed during degradation in aqueous solutions (hydrolysis, oxidation, phosphate buffer pH ∼6.0) and in the solid state (photolysis, thermolysis in dry air and at an increased relative air humidity). The method was based on zero-crossing first-derivative spectrophotometry (λ=341 nm for tebipenem pivoxyl and λ=320 nm for tebipenem), which eliminated the overlapping caused by various degradation products. The selectivity of the method for determination of tebipenem pivoxyl and tepipenem during stability studies was an effect of lack of substituents containing π-bond system chromophores in degradation products. It was also confirmed by comparison of the experimental spectra sample with the theoretical UV spectra and their first derivatives which were obtained by using the density functional theory with the B3LYP hybrid functional and 6-31G(d,p) basis set. The method were linear in the concentration range 16.70-220.0 μg mL(-1) for tebipenem (λ=320 nm; r=0.9989) and 10.70-160.0 μg mL(-1) for tebipenem pivoxyl (λ=341 nm, r=0.9990). The limits of detection and quantitation were 4.72 and 15.60 μg mL(-1) for tebipenem and 2.54 and 8.40 μg mL(-1) for tebipenem pivoxyl, respectively. The method had a good intra-day precision (RSD from 0.12% to 0.62%) and inter-day precision (RSD from 0.22% to 2.13%). The recovery of tebipenem and tebipenem pivoxyl ranged from 99.61% to 99.86% and from 99.38% to 99.87%, respectively. First-derivative spectrophotometry was used for a routine analysis of tebipenem and its ester as well as to monitor the conversion of tebipenem pivoxyl to tebipenem and to predict their degradation pathways.

Stability of cefozopran hydrochloride in aqueous solutions

Abstract The influence of pH on the stability of cefozopran hydrochloride (CZH) was investigated in the pH range of 0.44–13.00. Six degradation products were identified with a hybrid ESI-Q-TOF mass spectrometer. The degradation of CZH as a result of hydrolysis was a pseudo-first-order reaction. As general acid–base hydrolysis of CZH was not occurred in the solutions of hydrochloric acid, sodium hydroxide, acetate, borate and phosphate buffers, kobs = kpH because specific acid–base catalysis was observed. Specific acid–base catalysis of CZH consisted of the following reactions: hydrolysis of CZH catalyzed by hydrogen ions (kH+), hydrolysis of dications (k1H2O), monocations (k2H2O) and zwitter ions (k3H2O) and hydrolysis of zwitter ions (k1OH−) and monoanions (k2OH−) of CZH catalyzed by hydroxide ions. The total rate of the reaction was equal to the sum of partial reactions: . CZH similarly like other fourth generation cephalosporin was most stable at slightly acidic and neutral pH and less stable in alkaline pH. The cleavage of the β-lactam ring resulting from a nucleophilic attack on the carbonyl carbon in the β-lactam moiety is the preferred degradation pathway of β-lactam antibiotics in aqueous solutions.