Comparative Pharmaceutical Evaluation of Candesartan and Candesartan Cilexetil: Physicochemical Properties, In Vitro Dissolution and Ex Vivo In Vivo Studies

Abstract

The aim of the present work is to answer the question is it possible to replace the ester prodrug candesartan cilexetil (CC) by its active metabolite candesartan (C) to bypass the in vivo variable effect of esterase enzymes. A comparative physicochemical evaluation was conducted through solubility, dissolution, and stability studies; additionally, ex vivo permeation and in vivo studies were assessed. C demonstrated higher solubility over CC at alkaline pH. Moreover, dissolution testing using the pharmacopeial method showed better release profile of C even in the absence of surfactant in the testing medium. Both drugs demonstrated a slight degradation in acidic pH after short-term stability. Instead, shifting to alkaline pH of 6.5 and 7.4 showed superiority of C solution stability compared to CC solution. The ex vivo permeation results demonstrated that the parent compound C has a significant (P < 0.05) enhanced permeation compared to its prodrug from CC, that agreed with in vivo results in which C suspension reached significantly (P < 0.05) higher C of 1.39 ± 0.59 μg/mL at T of 0.66 ± 0.11 h, while CC suspension reached C of 0.47 ± 0.22 μg/mL at T of 2.00 ± 0.27 h, a lag period of 40 min is needed prior to detection of any absorbed CC in plasma. Those findings are not in agreement with the previously reported rationale on the prodrug formation owing to the poor permeability of the parent compound, suggesting the possibility of marketing the parent drug candesartan for clinical use similarly to azilsartan and its prodrug.

Solid State Stability and Kinetics of Degradation for Candesartan—Pure Compound and Pharmaceutical Formulation

“…The absorption bands that appeared in the range of 1640-1335 cm −1 were due to the stretching, while the ones occurring in the 1200-900 cm −1 range were due to skeletal vibrations of the cycle, as well as by the combination bands. The data were assigned according to literature [54] and were in good agreement with previously reported studies [36,[55][56][57].…”

“…In 2014, Moisei et al reported a compatibility study between several antihypertensive APIs and showed that CC is compatible with croscarmellose sodium, magnesium stearate and colloidal silica [35]. Amer et al [36] realized a comparative evaluation of candesartan and CC by means of physicochemical properties and in vitro dissolution studies in order to replace the ester prodrug candesartan cilexetil (CC) by its active metabolite candesartan, and the results were promising. Tita et al reported on the thermal behavior of candesartan, active substance and in pharmaceutical compounds in a dynamic nitrogen atmosphere in non-isothermal conditions, but they did so without mentioning any data regarding the strength of investigated pharmaceutical formulations and without clearly indicating if candesartan or candesartan cilexetil were studied as pure APIs; the paper mentions the cilexetil prodrug, but, though the chemical structure of the drug corresponds to candesartan, it does not correspond to the cilexetil derivative [37].…”

New Peceol™/Span™ 60 Niosomes Coated with Chitosan for Candesartan Cilexetil: Perspective Increase in Absolute Bioavailability in Rats

“…Our results were controversial to those described in previous literature. 65 This literature reported that CDT as a parent drug was better in bioavailability (higher C max and AUC) than CC as prodrug. These results were contrary to our findings.…”

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

“…Candesartan cilexetil is a prodrug of candesartan that was designed to increase its bioavailability and it is hydrolyzed to candesartan during absorption. Nevertheless, a recent study challenged this hypothesis by proposing the superior solubility and permeability of candesartan versus the prodrug [6].…”