The Effect of Polysorbate 20 on Solubility and Stability of Candesartan Cilexetil in Dissolution Media

Abstract

The addition of polysorbate 20 (T20) is required to achieve “sink” conditions during a dissolution test for tablets with candesartan cilexetil (CC). Polysorbate 20 (0.35%–0.7% w/w) added to 0.05 mol/L of phosphate buffer pH 6.5 dramatically increased the apparent solubility of the drug from 0.8 μg/ml even to 353 μg/ml, while its effect in lower pH or in water was much smaller (20 μg/ml in pH 4.5). The increased concentration of phosphate salts (0.2 mol/l) at pH 6.5 in the presence of 0.7% of polysorbate 20, resulted in further increase of candesartan cilexetil solubility to 620 μg/ml. The change of pH from 1.2 to 7.4 resulted in a 1.5-fold increase of the activation energy and, depending on temperature, 8–14-fold decrease of the degradation rate. When polysorbate 20 increased the activation energy 2-fold, independent of pH, it protected candesartan cilexetil from degradation; however, this effect was temperature dependent and was very small at 310 K—the degradation rate in pH 6.5 decreased by 13% only. It was calculated that in the phosphate buffer pH 6.5 with polysorbate, one can expect during 24 h the degradation at the level of 9.3%, thus a flow-through dissolution apparatus was recommended for testing prolonged release dosage forms.

Biorelevant dissolution of candesartan cilexetil

“…Despite the volume reduction, sink conditions were maintained in medium PPT20 regarding on our solubility data of CC. These data verify findings reported by Hoppe and Sznitowska [18].…”

“…CC was added in excess into specific solvent and shaken for 24 hours at 37 °C in a thermostated orbital platform shaker (Heidoplh, Unimax 1010 with Incubator 1000) to obtain equilibrium solubility [18,19]. Due to the low stability of CC, a 'shortened shake flask method' was suggest, the shaken time of certain saturated solutions, namely with solvents SGF, FaSSGF and SGF Triton , was only 2 hours or 12 hours.…”

“…The most important factors affecting the stability of CC in solution are pH and temperature. Hoppe and Sznitowska [18] found out that the degradation rate of CC was faster at elevated temperatures and low pHs. According to their results, the half-life of degradation is only 35.91 hours in 0.1 M HCl (pH 1.2) and 150.7 hours in 0.05 M phosphate buffer (pH 6.5), both at 37 °C and without surfactants [18].…”

Screening Study for Formulation Variables in Preparation and Characterization of Candesartan Cilexetil Loaded Nanostructured Lipid Carriers

“…In-vitro release study was achieved for all formulations in addition to pure CC suspension. The release condition monitored in 0.1 M HCl (pH 1.2) and PBS (pH 6.8) and at the same conditions with adding tween 20 (0.35%-0.7%w/w) to achieve "sink" conditions during a dissolution test for all formulations 54,55 . It was found that all formulations exhibit a lack of drug release within 24 h. The in-vitro release of the best formula (CC-NLC9) was reached to less than 5% as showed in (figure 6) but, CC suspension showed almost complete drug release (100%) within 8 h. As CC had solubility equal to 11 μg/ml in 0.1 M HCl and 1 μg/ml in PBS (pH 6.8).…”

Use of compounded dispersing media for extemporaneous pediatric syrups with candesartan cilexetil and valsartan

“…Previously described methods for determination of VAL (18)(19)(20) and CAN (21,22) in dosage forms were employed, with minor modifications. It was confirmed that the method was specific and accurate in the presence of syrup components.…”