Formulation development, in vivo bioequivalence and pediatric PBPK modeling studies of taste-masked ciprofloxacin chewable tablets

Abstract

A taste-masked chewable tablet of ciprofloxacin using ion exchange resin Kyron T-134 for enhancing compliance for the paediatric population was developed. The drug-to-resin ratio was optimized for maximum taste masking by studying the effects of soaking time (X1) and mixing time (X2) on complexation (%) using Central Composite Rotatable Design (CCRD). The resin complexes were characterized by bitterness score, DSC, FTIR, and PXRD. The complex was further formulated and optimized into chewable tablets through full factorial design, The optimized formulation was subjected to a bioequivalence study, and a virtual approach of PBPK modelling was adapted to predict the pharmacokinetics of the drug in the paediatric group. The drug resin ratio of 1:1.5 yielded an optimum drug loading of 99.05%. The optimized formulation shows minimum disintegration time with more than 99% drug release within 30 min. The formulation F-9 was found to be bioequivalent with a geometric mean ratio of C_max, T_max, AUC_0-t, and AUC_0-∞ within 90% CI. It was concluded that quality by design approach can successfully be applied to optimize the drug resin ratio and PBPK modeling is a successful predictive tool for estimating the pharmacokinetics of ciprofloxacin HCl in the paediatric population.

Figure 1

(A) Chemical structure of Ciprofloxacin hydrochloride (B) Polacrilin potassium.

Figure 2

Response surface showing relationship of (a) drug:resin ratio and percent complexation. (b) Independent variables (soaking and mixing time) and drug complexation. (c) Independent variables (Croscarmellose Sodium and SLS) and disintegration time. (d) Independent variables (Croscarmellose Sodium and SLS) and dissolution.

Figure 3

FTIR spectra of (a). Ciprofloxacin (API) (b) Kyron T-134 (c) Ciprofloxacin–Kyron physical mixture and (d) Ciprofloxacin–Kyron complex.

Figure 4

X-ray diffractograms of (a). Ciprofloxacin (API) (b) Kyron T-134 (c) Ciprofloxacin–Kyron physical mixture and (d) Ciprofloxacin–Kyron complex.

Figure 5

DSC thermograms of individual components of drug resin complex and optimized complex.

Figure 6

Comparative dissolution profile of Ciprofloxacin chewable tablets and Ciproxin tablets in 0.1N HCl.

Figure 7

Comparative dissolution profile of Ciprofloxacin chewable tablets and Ciproxin tablets in Acetate Buffer pH 4.5.

Figure 8

Comparative dissolution profile of Ciprofloxacin chewable tablets and Ciproxin tablets in Phosphate buffer pH 6.8.

Figure 9

Mean ± SD plot of plasma concentration versus time profile comparison of Ciprofloxacin reference product (Ciproxin 250 mg) and Ciprofloxacin chewable tablets (Test F9) under fasted condition.

Figure 10

Comparison of observed and predictive Time plasma concentration of Ciprofloxacin 250 mg in (a) IV bolus adults (b) oral in adults in fasted conditions (c) oral in adults in fed conditions (d) oral for paediatric in pH 1.2 (e) oral for paediatric in pH 4.5 (f) oral for paediatric in pH 6.8.