Alicja Talaczyńska

Prediction of HPLC retention times of tebipenem pivoxyl and its degradation products in solid state by applying adaptive artificial neural network with recursive features elimination

A sensitive and fast HPLC method using ultraviolet diode-array detector (DAD)/electrospray ionization tandem mass spectrometry (Q-TOF-MS/MS) was developed for the determination of tebipenem pivoxyl and in the presence of degradation products formed during thermolysis. The chromatographic separations were performed on stationary phases produced in core-shell technology with particle diameter of 5.0 µm. The mobile phases consisted of formic acid (0.1%) and acetonitrile at different ratios. The flow rate was 0.8 mL/min while the wavelength was set at 331 nm. The stability characteristics of tebipenem pivoxyl were studied by performing stress tests in the solid state in dry air (RH=0%) and at an increased relative air humidity (RH=90%). The validation parameters such as selectivity, accuracy, precision and sensitivity were found to be satisfying. The satisfied selectivity and precision of determination were obtained for the separation of tebipenem pivoxyl from its degradation products using a stationary phase with 5.0 µm particles. The evaluation of the chemical structure of the 9 degradation products of tebipenem pivoxyl was conducted following separation based on the stationary phase with a 5.0 µm particle size by applying a Q-TOF-MS/MS detector. The main degradation products of tebipenem pivoxyl were identified: a product resulting from the condensation of the substituents of 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-azetidinyl]sulfanyl and acid and ester forms of tebipenem with an open β-lactam ring in dry air at an increased temperature (RH=0%, T=393 K) as well as acid and ester forms of tebipenem with an open β-lactam ring at an increased relative air humidity and an elevated temperature (RH=90%, T=333 K). Retention times of tebipenem pivoxyl and its degradation products were used as training data set for predictive model of quantitative structure-retention relationship. An artificial neural network with adaptation protocol and extensive feature selection process was created. Input parameters for model were calculated from molecular geometries optimized with application of Density Functional Theory. The model was prepared and optimized especially for small data sets such as degradation products of specific compound. Validation of the model with statistical test against requirements for QSAR showed its ability for prediction of retention times within given data set. Mean error of 24.75% (0.8 min) was achieved with utilization of topological, geometrical and electronic descriptors.

Benefits and Limitations of Polymorphic and Amorphous Forms of Active Pharmaceutical Ingredients

Active pharmaceutical ingredients (APIs) can exist in different polymorphic forms as well as in amorphous state. Polymorphic and amorphous forms of APIs can differ in physicochemical properties which in turn can significantly influence their therapeutic safety and effectiveness of the treatment. This review focuses on benefits and limitations of polymorphic and amorphous forms of APIs used in preformulation and formulation studies. Authors present their work on safety precautions for the use of polymorphic and amorphous forms of APIs, analytical techniques used for their identification as well as methods of their preparation especially in regard to limitations of labile APIs.

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.

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.

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.

Solid-state stability studies of crystal form of tebipenem

Abstract The aim of this study was to determine the kinetic and thermodynamic parameters of tebipenem degradation in the solid state. The process was analyzed based on the results obtained by a high performance liquid chromatography (HPLC) method using ultraviolet diode-array detector (DAD)/electrospray ionization tandem mass spectrometry (Q-TOF-MS/MS), Fourier transform infrared spectroscopy (FT-IR) and Raman spectroscopic (RS) studies. In dry air, the degradation of tebipenem was a first-order reaction depending on the substrate concentration while at an increased relative air humidity tebipenem was degraded according to the kinetic model of autocatalysis. The thermodynamic parameters: energy of activation (Ea), enthalpy (ΔH≠a) and entropy (ΔS≠a) of tebipenem degradation were calculated. Following a spectroscopic analysis of degraded samples of tebipenem, a cleavage of the β-lactam bond was proposed as the main degradation pathway, next confirmation using HPLC-Q-TOF-MS/MS method.

Computational study of influence of diffuse basis functions on geometry optimization and spectroscopic properties of losartan potassium.

The work was aimed at investigating the influence of diffusion of basis functions on the geometry optimization of molecule of losartan in acidic and salt form. Spectroscopic properties of losartan potassium were also calculated and compared with experiment. Density functional theory method with various basis sets: 6-31G(d,p) and its diffused variations 6-31G(d,p)+ and 6-31G(d,p)++ was used. Application of diffuse basis functions in geometry optimization resulted in significant change of total molecule energy. Total molecule energy of losartan potassium decreased by 112.91kJ/mol and 114.32kJ/mol for 6-31G(d,p)+ and 6-31G(d,p)++ basis sets, respectively. Almost the same decrease was observed for losartan: 114.99kJ/mol and 117.08kJ/mol respectively for 6-31G(d,p)+ and 6-31G(d,p)++ basis sets. Further investigation showed significant difference within geometries of losartan potassium optimized with investigated basis sets. Application of diffused basis functions resulted in average 1.29Å difference in relative position between corresponding atoms of three obtained geometries. Similar study taken on losartan resulted in only average 0.22Å of dislocation. Extensive analysis of geometry changes in molecules obtained with diffused and non-diffuse basis functions was carried out in order to elucidate observed changes. The analysis was supported by electrostatic potential maps and calculation of natural atomic charges. UV, FT-IR and Raman spectra of losartan potassium were calculated and compared with experimental results. No crucial differences between Raman spectra obtained with different basis sets were observed. However, FT-IR spectra of geometry of losartan potassium optimized with 6-31G(d,p)++ basis set resulted in 40% better correlation with experimental FT-IR spectra than FT-IR calculated with geometry optimized with 6-31G(d,p) basis set. Therefore, it is highly advisable to optimize geometry of molecules with ionic interactions using diffuse basis functions when accuracy of results is a priority.

[Meropenem--therapeutic recommendation after twenty years of presence on pharmaceutical market].

Meropenem is the first representative of carbapenem analogues with methyl group, which has been applied in medicine. This drug has been approved by FDA (Food and Drug Administration) in 1996. Available results of clinical trials and scientific reports point surprising synergism of combination of meropenem with other chemotherapeutics, in the treatment of bacterial diseases. Present study based on available information presents indications for use the mentioned antibiotic in pharmacotherapy of infectious diseases. Meropenem is the first representative of carbapenem analogues, which contains methyl group. Introduction of a methyl group at the system of coupled rings: β-lactam and pyrrolidine, solved the problem of degradation by the dehydropeptidase-I (DHP-I). In the consequence it is not necessary to use meropenem in the connection with specific DHP-I inhibitors. Meropenem, similarly to other carbapanem analogues, is intended for the treatment of severe inpatient and outpatient infections. Bacterial resistance to meropenem may be the result of: carbapenemases activity, decreased affinity to Penicillin Binding Proteins--PBP (mainly PBP 2 and PBP 3) and activation of efflux pump (antibiotic ejection outside the cell). Twenty-year period of application of meropenem in pharmacotherapy may cause the spread of methyl-β-lactamases.