Formulation development and optimization of taste-masked azithromycin oral suspension with ion exchange resins: Bioanalytical method development and validation, in vivo bioequivalence study, and in-silico PBPK modeling for the paediatric population

Publication: J Drug Deliv Sci Technol
Software: GastroPlus®


The study is based on preparing taste-masked oral suspension of azithromycin using ion exchange resins Kyron T135 and Doshion-P542 AB. The complexation process was optimized through Design of Experiment (DOE), and the resins-complexes were characterized by bitterness score, differential scanning calorimetry (DSC), fourier transform infra-red spectrophotometry (FTIR) and powder x-ray diffraction (PXRD). The complexes were further formulated and optimized through Central Composite Design (CCRD) into oral suspension using xanthan gum, hydroxypropyl cellulose, tri-basic sodium phosphate, and sucrose. To obtain the optimized product, the trial batches were tested for sedimentation ratio and viscosity in comparison to the reference product followed by assay and studies of drug-release kinetics. To perform bioequivalence of the optimized formulations against the reference product, an LC-MS/MS based bio-analytical method was developed and validated followed by a three-period cross over study. The pharmacokinetic parameters Cmax, Tmax, AUC0-t and AUC 0-∞ were obtained through non-compartmental analysis (NCA) using log-transformed data. Moreover, physiologically based pharmacokinetic (PBPK) modelling of the in-vitro data was carried out to predict the pharmacokinetics of the optimized formulations in the intended paediatric population. Kyron T-135 yielded the best loading efficiency at a drug resin ratio of 1:1.35 and Doshion-P542 AB at 1:3.25, while stirring and swelling time of 30 min for Kyron T-135 yielded optimum drug loading. In case of Doshion P-542 AB the optimum time was 22.5 and 30 min for stirring and swelling respectively. The bitterness score proved the tastelessness of the drug resin complex. The optimized formulation with Kyron (formulation code K4) and Doshion (formulation code D6) were selected as optimum on the basis of similar quality attributes to the reference product. The drug dissolution kinetics revealed first order drug release. The developed bioanalytical method was found to be sensitive and linear in the range of 2–500 ng/mL showing accuracy within 101.32–106.68%. Both optimized formulations (K4 and D6) were found to be bioequivalent with geometric mean ratio of Cmax, Tmax, AUC0-t and AUC 0-∞ within 90% C.I. in silico PBPK based predictive pharmacokinetics in the paediatric population was successfully estimated for the developed formulations.

By Fahad Siddiqui, Muhammad Harris Shoaib, Farrukh Rafiq Ahmed, Faaiza Qazi, Rabia IsmailYousuf, Muhammad Talha Usmani, Muhammad Talha Saleem & Kamran Ahmed