Andjelija Malenovic

Advancement in optimization tactic achieved by newly developed chromatographic response function: application to LC separation of raloxifene and its impurities.

In this paper a new chromatographic response function (CRF) is designed and proposed for utilization in the optimization strategies. The function capability to represent the overall quality of a experimentally obtained chromatograms was compared to the other two objective functions and proved to give more accurate and reliable results. The new CRF has improved concept of separation and time term estimation. It reflects all important defects of the chromatogram such as the appearance of asymmetrical or overlapping peaks and prolonged elution time and allows the appropriate weighting of each of them. The LC separation of raloxifene and its four impurities was evaluated through the central composite design experimental plan choosing the new CRF to be the only output of the system. The function demonstrated the ability to judge the impact of the complex interactions of the selected chromatographic parameters (acetonitrile content in the mobile phase, sodium dodecyl sulfate concentration in the water phase, pH of the mobile phase and column temperature) on the mixture behavior and led to the determination of the optimal separation conditions. The newly developed CRF proved to have the advanced performances and it presents the important step forward in the optimization of the chromatographic separation.

Ibuprofen sorption and release by modified natural zeolites as prospective drug carriers

Abstract The sorption of ibuprofen by modified natural zeolite composites at three concentration levels (10, 20 and 30 mmol/100 g) of cationic surfactants - benzalkonium chloride and cetylpyridinium chloride, in a buffer solution (pH 7.4), was studied. Characterization of the composites before and after ibuprofen sorption was performed by drug sorption and isotherm studies, zeta potential and Fourier Transform infrared spectroscopic analysis. The biopharmaceutical performance of cationic surfactant-modified zeolites as drug formulation excipients was evaluated by in vitro dissolution experiments from the composites with medium surfactant contents. The drug sorption was influenced by the surfactant type and amount used for the zeolite modification. Prolonged drug release over a period of 8 h (up to ~40%) was achieved with both groups of samples. The kinetic analysis showed that the drug release profiles were best fitted with the Higuchi and the Bhaskar models, indicating a combination of drug diffusion and ion exchange as the predominant release mechanisms.

Artificial neural networks in analysis of indinavir and its degradation products retention

Artificial neural networks (ANN) are biologically inspired computer programs designed to simulate the way in which the human brain processes the information. In the past few years, coupling of experimental design (ED) and ANN became useful tool in the method optimization. This paper presents the application of ED-ANN in analysis of chromatographic behavior of indinavir and its degradation products. According to preliminary study, full factorial design 2(4) was chosen to set input variables for network training. Experimental data (inputs) and results for retention factors from experiments (outputs) were used to train the ANN with aim to define correlation among variables. For networks training multi-layer perceptron (MLP) with back propagation (BP) algorithm was used. Network with the lowest root mean square (RMS) had 4-8-3 topology. Predicted data were in good agreement with experimental data (correlation was higher than 0.9713 for training set). Regression statistics confirmed good ability of trained network to predict compounds retention.

The Second-Derivative Spectrophotometric Assay of a Multicomponent Analgetic Mixture

Abstract In this paper the second-derivative spectrophotometric method for the simultaneous determination of some analgetic ingredients was described. Optimal conditions for the quantitative analysis of the three-component analgetic mixture of Dalivon® tablets were settled. The second-derivative order of the spectra in sodium hydroxide with the wavelength modulation was used. For the determination of paracetamol the “zero-crossing” technique was applied, but for propyphenazone and caffeine the characteristic peak amplitude had to be corrected. The authors propose this second-derivative spectrophotometry for a rapid, simple, precise and accurate determination of the Dalivon® tablets or a corresponding multicomponent mixture.

Optimization of an RP‐HPLC Method for Drug Control Analysis

Abstract Optimization of important conditions for the reversed‐phase high‐performance liquid chromatographic method was done for the separation of the active ingredients in Marcaine® adrenaline injections (bupivacaine hydrochloride 2.5 mg and adrenaline 5.0 µg). Simultaneous influence of several conditions, such as the mobile phase composition, pH of the mobile phase, and temperature, on important chromatographic criteria for the separation, was investigated. The separation factor values defined the optimal conditions, which were confirmed by analysing the appropriate mathematical models. The 3‐D graphs, constructed with sixty‐four experimental points, were investigated, and the results showed that the optimal separation was achieved with the mobile phase of methanol–water (65:35 v/v), by adjusting pH to 3.5 and the temperature range from 20°C to 30°C. The optimized method was validated and the obtained results were statistically evaluated.

INVESTIGATION OF TROPICAMIDE AND BENZALKONIUM CHLORIDE STABILITY USING LIQUID CHROMATOGRAPHY

In this study, a development of stability indicating method (SIM) that could be used to detect a decrease in the amount of tropicamide and benzalkonium chloride due to their degradation is described. In the method development, stress samples should be used. Benzalkonium chloride proved to be very stable under all stress conditions. Acid stress with 0.1 M HCl at 70°C led to 10% degradation of tropicamide after 30 min. The alkaline stress with 1 M NaOH at 70°C induced faster degradation and more than 20% of tropicamide degraded after 30 min. On the other hand, tropicamide proved to be exceptionally stable to oxidative stress and no degradation was observed with 30% H2O2 even after heating at 70°C for 90 min. The mobile phase consisted of acetonitrile and water phase 70:30 v/v (water phase: 5 mM sodium heptan sulphonate and 1% triethylamine – TEA) with pH of the mobile phase adjusted to 3.5 with ortophosphoric acid. The flow rate was 2 mL min−1. In order to confirm the method adequacy for intended purpose, the proposed method was validated. Finally, the proper validation of developed SIM performed according to the official guidelines proved that the method accomplishes its intended purpose.

Evaluation of RP-HPLC Method Intended for the Analysis of Cefuroxime Axetil and ITS Impurities Supported by Experimental Design

In this paper, a chemometrically assisted validation of RP-HPLC method, intended for the quantitative analysis of cefuroxime axetil (A and B), cefuroxime acid, cefuroxime lactone, cefuroxime axetil sulfoxide (A and B), ∆3-cefuroxime axetil and anti cefuroxime axetil (A and B) in tablets, is presented. Since the successful separation could be achieved with the mobile phase containing only methanol and water, Luna C18 column was selected for the analysis. Under these circumstances, the optimization was quite straightforward and included only a fine tuning of the chromatographic conditions to reduce total run time and maintain the achieved separation. The established method was then subjected to the method validation and the required validation parameters were tested. For the robustness evaluation, a fractional factorial 24−1 design was utilized and factors that might significantly affect the system performance were defined. For the significant factors, the non-significant intervals were determined and the acceptable system suitability limit for resolution factor between cefuroxime axetil A and cefuroxime axetil ∆3 isomer (R2) was calculated. As the other validation parameters were also found to be suitable, the possibility to apply the proposed method for the determination of cefuroxime axetil, cefuroxime acid, cefuroxime lactone, cefuroxime axetil sulfoxide, ∆3-cefuroxime axetil and anti cefuroxime axetil in any laboratory under different circumstances is proven.

Demasking large dummy effects approach in revealing important interactions in Plackett–Burman experimental design

This paper presents a newly developed demasking large dummy effects (DDE) approach for identification of significant factor interactions in Plackett–Burman experimental design. Dummy factors, as imaginary factors, are not expected to contribute to the model, so the appearance of their high effect values could indicate the significance of the interactions they are confounded with. DDE approach consists of the screening of the large estimable effects, the calculation of the interactions that contribute the most to the large dummy effects from the alias matrix, and a single pass of all subsets regressions including preselected interactions and main factors for the final model tuning.