Development of Analytical Quality by Design Compliant Chaotropic Chromatography Method for Ziprasidone and Its Five Impurities Determination.

In this study, an AQbD-compliant chaotropic chromatography method for ziprasidone and the determination of its five impurities was developed. The influence of critical method parameters (initial and final methanol fraction in the mobile phase, gradient duration) on the set of selected critical method attributes (t_imp. V, t_imp. V - t_imp. I, S and ) was studied by Box-Behnken design. The errors resulting from the calculation of the model coefficients were propagated to the selected responses by Monte Carlo simulations, and their predictive distribution was obtained. The design space was computed (π ≥ 80%), and a working point was selected: initial methanol fraction 38.5%, final methanol fraction 77.5%, and gradient duration 16.25 min. Furthermore, the quantitative robustness of the developed method was tested using the Plackett-Burman design. P_imp II and P_imp V were found to be significantly affected, the first by mobile phase flow rate and the second by gradient duration. Finally, the method was validated, and its reliability for routine quality control in capsules was confirmed.

Evaluation of chitosan/xanthan gum polyelectrolyte complexes potential for pH-dependent oral delivery of escin.

Escin is an amphiphilic and weakly acidic drug that oral administration may lead to the irritation of gastric mucosa. The entrapment of escin into chitosan (CH)/xanthan gum (XG)-based polyelectrolyte complexes (PECs) can facilitate controlled drug release which may be beneficial for the reduction of its side effects. This study aimed to investigate the influence of escin content and drying method on the formation, physicochemical, and controlled, pH-dependent drug release properties of CH/XG-based PECs. Measurements of transmittance, conductivity, and rheological characterization confirmed the formation of CH/XG-based PECs with escin entrapped at escin-to-polymers mass ratios 1:1, 1:2, and 1:4. Ambient-dried PECs had higher yield, entrapment efficiency, and escin content in comparison with spray-dried ones. FT-IR spectra confirmed the interactions between CH, XG, and escin, which were stronger in ambient-dried PECs. PXRD and DSC analyses showed the amorphous escin character in all dry PECs, regardless of the drying method. The most promising controlled and pH-dependent in vitro escin release was from the ambient-dried PEC at the escin-to-polymers mass ratio of 1:1. For that reason and due to the highest yield and entrapment efficiency, this carrier has the potential to prevent the irritation of gastric mucosa after oral administration of escin.

Quantification of Zonisamide in Dried Blood Spots and Dried Plasma Spots by UPLC-MS/MS: Application to Clinical Practice.

In this research, a UHPLC-MS/MS method was developed and validated for the determination of zonisamide in dried plasma spots (DPS) and dried blood spots (DBS). Detection of zonisamide and internal standard, 1-(2,3-dichlorphenyl)piperazine, was carried out in ESI+ mode by monitoring two MRM transitions per analyte. Total run time, less than 2.5 min, was achieved using Acquity UPLC BEH Amide (2.1 × 100 mm, 1.7 µm particle size) column with mobile phase comprising acetonitrile-water (85:15%, v/v) with 0.075% formic acid. The flow rate was 0.225 mL/min, the column temperature was 30 °C and the injection volume was 3 µL. Desolvation temperature, desolvation gas flow rate, ion source temperature and cone gas flow rate were set by the IntelliStart software tool in combination with tuning. All of the Guthrie cards were scanned, and DPS/DBS areas were determined by the image processing tool. The influence of hematocrit values (20-60%) on accuracy and precision was evaluated to determine the range within which method for DBSs is free from Hct or dependency is within acceptable limits. The validated method was applied to the determination of zonisamide levels in DPS and DBS samples obtained from patients confirming its suitability for clinical application. Finally, the distribution of zonisamide into the red blood cells was estimated by correlating its DPS and DBS levels.

Effect of ibuprofen entrapment procedure on physicochemical and controlled drug release performances of chitosan/xanthan gum polyelectrolyte complexes.

The effect of the entrapment procedure of a poorly water soluble drug (ibuprofen) on physicochemical and drug release performances of chitosan/xanthan polyelectrolyte complexes (PECs) was investigated to achieve controlled drug release as the ultimate goal. The formation of PECs for two drug entrapment procedures (before or after the mixing of polymers) at pH 4.6 and 5.6 and three chitosan-to-xanthan mass ratios (1:1, 1:2 and 1:3) was observed by continuous decrease in conductivity during the PECs formation and increased apparent viscosity and hysteresis values. The most extensive crosslinking was observed with ibuprofen added before the PECs formation at pH 4.6 and chitosan-to-xanthan mass ratio 1:1. The PECs prepared at polymers' mass ratios 1:2 and 1:3 had higher yield and drug entrapment efficiency. DSC and FT-IR analysis confirmed ibuprofen entrapment in PECs and the partial disruption of its crystallinity. All ibuprofen release profiles were similar, with 60-70% of drug released after 12 h, mainly by diffusion, but erosion and polymer chain relaxation were also included. Potentially optimal can be considered the PEC prepared at pH 4.6, ibuprofen entrapped before the mixing of polymers at chitosan-to-xanthan mass ratio 1:2, which provided controlled drug release by zero-order kinetics, high yield, and drug entrapment efficiency.

Chaotropic chromatography method development for the determination of aripiprazole and its impurities following analytical quality by design principles.

In this paper, development of robust and reliable chaotropic chromatography method for the determination of aripiprazole and its impurities, following Analytical Quality by Design principles is presented. The efficient baseline separation and accurate determination of aripiprazole and its four impurities from tablets were set as Analytical Target Profile. In line with it, the influence of Critical Method Parameters (acetonitrile content, concentration of perchloric acid in water phase, and column temperature) on predefined Critical Method Attributes (separation of the critical pair of peaks, retention of the first and last eluting peak) was investigated with aid of the Central Composite Design. Further on Design Space, where Critical Method Parameters meet predefined acceptance limits with a high level of probability (π ≥ 85%), was computed as a result of performed Monte Carlo simulations. A normal operating conditions corresponding to 34% of acetonitrile, 66% of 42.5 mM perchloric acid, and column temperature at 35°C were selected from created Design Space. Robustness testing of the quantitative performances of the developed method was conducted combining Plackett-Burman design with alias matrix approach. Through the additional validation testing, reliability of the developed method for the use in the routine practice was completely confirmed.

Characterization of bonded stationary phase performance as a function of qualitative and quantitative chromatographic factors in chaotropic chromatography with risperidone and its impurities as model substances.

Numerous stationary phases have been developed with the aim to provide desired performances during chromatographic analysis of the basic solutes in their protonated form. In this work, the procedure for the characterization of bonded stationary phase performance, when both qualitative and quantitative chromatographic factors were varied in chaotropic chromatography, was proposed. Risperidone and its three impurities were selected as model substances, while acetonitrile content in the mobile phase (20-30%), the pH of the aqueous phase (3.00-5.00), the content of chaotropic agents in the aqueous phase (10-100 mM), type of chaotropic agent (NaClO4, CF3COONa), and stationary phase type (Zorbax Eclipse XDB, Zorbax Extend) were studied as chromatographic factors. The proposed procedure implies the combination of D-optimal experimental design, indirect modeling, and polynomial-modified Gaussian model, while grid point search method was selected for the final choice of the experimental conditions which lead to the best possible stationary phase performance for basic solutes. Good agreement between experimentally obtained chromatogram and simulated chromatogram for chosen experimental conditions (25% acetonitrile, 75 mM of NaClO4, pH 4.00 on Zorbax Eclipse XDB column) confirmed the applicability of the proposed procedure. The additional point was selected for the verification of proposed procedure ability to distinguish changes in solutes' elution order. Simulated chromatogram for 21.5% acetonitrile, 85 mM of NaClO4, pH 5.00 on Zorbax Eclipse XDB column was in line with experimental data. Furthermore, the values of left and right peak half-widths obtained from indirect modeling were used in order to evaluate performances of differently modified stationary phases applying a half-width plots approach. The results from half-width plot approach as well as from the proposed procedure indicate higher efficiency and better separation performance of the stationary phase extra densely bonded and double end-capped with trimethylsilyl group than the stationary phase with the combination of end-capping and bidentate silane bonding for chromatographic analysis of basic solutes in RP-HPLC systems with chaotropic agents. Graphical abstract ᅟ.