Formulation Optimization and In-Vivo Characterization of Extended Release Tablets Containing Weakly Basic Drug Using Qbd

Abstract

In formulation development, extended release of weakly basic drug offers a major challenge. Weakly basic drugs and their salts exhibit drop in solubility at higher pH conditions leading to low and incomplete drug release and the drug release rates are strongly dependent on pH of dissolution medium. The objective of this study was to formulate extended release matrix tablets consisting of Trz_11XA (pKa 6.74) by modulating matrix microenvironmental pH by incorporation of pH-modifiers and thus determining their relevance with regards to appropriate pH-independent drug release, process variables using QbD approach, in-vivo behaviour, IVIVC correlation and accelerated stability. After identifying Quality Target Product Profile and doing risk assessment, drug release of Trz_11XA from the hydrophilic matrices prepared using HPMC K 4M and PEO WSR 1105 was investigated. The effects of various polymeric pH-modifiers like Eudragit L100-55, Eudragit L 100, Protanal CR 8233 and Carbopol 71 G NF and non-polymeric pH-modifiers like Citric acid and Fumaric acid were also investigated. Optimization was carried out using 32 full factorial design and the optimized batch was further evaluated for effect of process variables, release kinetics, accelerated stab C/75%RH for 1 month). In-vivo plasma concentration and pharmacokinetic parameters were estimated in rabbits along with determination of IVIVC. HPMC K 4M was able to control drug release up to 24 hours in a better way as compared to PEO WSR 1105. Out of all pH-modifiers studied, Citric acid showed best pH-independent drug release and followed Korsmeyer-Peppas model for release kinetics. In-vivo pharmacokinetic parameters showed significant Level A correlation while stability was detected within the target range. It was concluded that mixture of HPMC K4 M and Citric acid was effective in formulating pH-independent extended release matrix tablets showing Level A IVIVC correlation with acceptable stability.