Investigation of Solvolysis Kinetics of New Synthesized Fluocinolone Acetonide C-21 Esters—An In Vitro Model for Prodrug Activation

Abstract

In this study the solvolysis of newly synthesized fluocinolone acetonide C-21 esters was analysed in comparison with fluocinonide during a 24-hour period of time. The solvolysis was performed in an ethanol-water (90:10 v/v) mixture using the excess of NaHCO3. The solvolytic mixtures of each investigated ester have been assayed by a RP-HPLC method using isocratic elution with methanol-water (75:25 v/v); flow rate 1 mL/min; detection at 238 nm; temperature 25 °C. Solvolytic rate constants were calculated from the obtained data. Geometry optimizations and charges calculations were carried out by Gaussian W03 software. A good correlation (R = 0.9924) was obtained between solvolytic rate constants and the polarity of the C-O2 bond of those esters. The established relation between solvolytic rate constant (K) and lipophilicity (cLogP) with experimental anti-inflammatory activity could be indicative for topical corticosteroid prodrug activation.

Synthesis, characterization, and in-vitro antitumor activity of the polyethylene glycol (350 and 1000) succinate derivatives of the tocopherol and tocotrienol isomers of Vitamin E

“…6). The most hydrophilic δ-T3 conjugates were hydrolyzed first followed by the γ-T3, α-T3 and α-T isomers in the order of their hydrophilicity, which was in agreement with the reported observations that enhanced polarity could improve hydration for the esters (Markovic et al, 2011). Due to their smaller size, however, isomers conjugated to mPEG 1000 had a slower hydrolysis rate.…”

Programmed Hydrolysis in Designing Paclitaxel Prodrug for Nanocarrier Assembly

“…In addition to this, Markovic et al established a good correlation (R = 0.9924) between solvolytic rate constants and polarity, indicating enhanced polarity could improve hydration for a prodrug 32 . It is reasonable to assume that the hydrolysis rate is dependent on polarity to some extent.…”

A PAMPA Assay as Fast Predictive Model of Passive Human Skin Permeability of New Synthesized Corticosteroid C-21 Esters

“…After the PAMPA tests was performed, a HPLC method was used to measure the concentrations of the investigated corticosteroids: the initial concentration– C D (0) in the starting solution, the residual concentration– C D (t) in the donor compartment (7 h after incubation) and the transferred concentration– C A (t) in the acceptor compartment (7 h after incubation). The assay was performed using the previously described HPLC method [ 29 ] with mobile phase modification for determination of standard corticosteroids. The mobile phase modification was introduced to achieve complete separation standard corticosteroids peak from DMSO peak, which was used as cosolvent.…”

“…In our previous paper [ 30 ] the anti-inflammatory activity of new fluocinolone acetonide C-21 esters was evaluated in the test of inhibition of croton oil induced mice ear edema (4 h after application). For the same group of FA C-21 esters in our recently published paper [ 29 ] it was established that the in vitro proposed solvolytic model, obtained by multiple regression analysis between solvolytic rate constant and lipophilicity with anti-inflammatory activity, could be used for prediction of prodrug activation. Anti-inflammatory activity [ 30 ], represented as a percentage of reduction of mass edema, has been determined using median effective dose ED 50 (28 μM) of FA [ 33 ].…”

“…In our recent papers the studies of solvolysis of new synthesized fluocinolone acetonide C-21 esters as in vitro model for predicting prodrug activation [ 29 ] and their topical anti-inflammatory activity [ 30 ] were reported. The aim of this study was to established membrane retentions, permeation parameters and effective permeability coefficients using PAMPA assay for twenty newly synthesized corticosteroid C-21 esters of standard corticosteroids: fluocinolone acetonide (FA), dexamethasone (DEX), triamcinolone acetonide (TA) and hydrocortisone (H).…”