Candesartan Cilexetil In Vitro–In Vivo Correlation: Predictive Dissolution as a Development Tool

Abstract

<jats:p>The main objective of this investigation was to develop an in vitro–in vivo correlation (IVIVC) for immediate release candesartan cilexetil formulations by designing an in vitro dissolution test to be used as development tool. The IVIVC could be used to reduce failures in future bioequivalence studies. Data from two bioequivalence studies were scaled and combined to obtain the dataset for the IVIVC. Two-step and one-step approaches were used to develop the IVIVC. Experimental solubility and permeability data confirmed candesartan cilexetil. Biopharmaceutic Classification System (BCS) class II candesartan average plasma profiles were deconvoluted by the Loo-Riegelman method to obtain the oral fractions absorbed. Fractions dissolved were obtained in several conditions in USP II and IV apparatus and the results were compared calculating the f2 similarity factor. Levy plot was constructed to estimate the time scaling factor and to make both processes, dissolution and absorption, superimposable. The in vitro dissolution experiment that reflected more accurately the in vivo behavior of the products of candesartan cilexetil employed the USP IV apparatus and a three-step pH buffer change, from 1.2 to 4.5 and 6.8, with 0.2% of Tween 20. This new model was able to predict the in vivo differences in dissolution and it could be used as a risk-analysis tool for formulation selection in future bioequivalence trials.</jats:p>

Developing pH-Modulated Spray Dried Amorphous Solid Dispersion of Candesartan Cilexetil with Enhanced In Vitro and In Vivo Performance

“…Polymers and other excipients must have good compatibility and affinity with the drug to achieve the desired in vitro dissolution rate, which is correlated to a favorable in vivo drug profile [9]. CC behaves like a weakly acidic drug and gets deprotonated in solutions with a high pH (pH > pKa), resulting increased solubility profile [39].…”

In vitro and in vivo correlation for lipid-based formulations: Current status and future perspectives

“…Great efforts have been made in the past to improve poor bioavailability of such compounds in an attempt to unlock their therapeutic potential as oral medicines and achieve some success 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 . The enhancement of dissolution and absorption is one of the enduring research topics in pharmaceutical researches 19 , 20 , 21 .…”

“…In vitro and in vivo correlations (IVIVCs) are powerful tools for optimizing the formulation and dosage, setting dissolution limits, and reducing bioequivalence (BE) studies 19 , 33 , 34 , 35 , 36 , 37 , 38 , 39 . By definition, an IVIVC is a mathematical model bridging in vitro properties and an in vivo response of a preparation 40 .…”

“…In vitro dissolution can be a surrogate for BE studies upon availability of an established IVIVC. Considerable interest in IVIVCs has been elicited in the pharmaceutical industry, academia, and regulatory sectors 20 , 38 , 41 , while dosage forms have been extended from oral extended-release to oral immediate-release forms 19 , 35 , 42 , 43 , 44 , 45 , 46 , 47 , modified-release parenteral dosage forms 36 , 47 , 48 , 49 , 50 , 51 , and transdermal DDSs 33 , 34 , 52 , 53 , 54 , 55 , 56 . Similarly, a reliable IVIVC model could promote the development of LBFs.…”

Regional Intestinal Drug Absorption: Biopharmaceutics and Drug Formulation

“…The GIT can be broadly divided to several regions: the stomach, the small intestine (which is subdivided into the duodenum, jejunum, and ileum), and the colon. The conditions and environment in each of these segments, and even within the segment, are dependent on many factors, e.g., the surrounding pH [ 1 , 2 , 3 , 4 , 5 , 6 ], fluid composition [ 7 , 8 , 9 ], transporters expression [ 10 , 11 , 12 ], metabolic enzymes activity [ 13 , 14 ], tight junction resistance [ 15 , 16 ], different morphology along the GIT [ 17 , 18 ], variable intestinal mucosal cell differentiation [ 19 , 20 ], changes in drug concentration (in cases of carrier-mediated transport), thickness and types of mucus [ 21 ], and resident microflora [ 22 , 23 , 24 ]. Each of these variables, alone or in combination with others, can fundamentally alter the solubility/dissolution, the intestinal permeability, and the overall absorption of various drugs [ 25 , 26 , 27 , 28 ].…”