Dissolution and precipitation behavior of ternary solid dispersions of ezetimibe in biorelevant media

Abstract

The effects of different formulations and processes on inducing and maintaining the supersaturation of ternary solid dispersions of ezetimibe (EZ) in two biorelevant media fasted-state simulated intestinal fluid (FaSSIF) and fasted-state simulated gastric fluid (FaSSGF) at different temperatures (25 °C and 37 °C) were investigated in this work. Ternary solid dispersions of EZ were prepared by adding polymer PVP-K30 and surfactant poloxamer 188 using melt-quenching and spray-drying methods. The resulting solid dispersions were characterized using scanning electron microscopy, differential scanning calorimetry (DSC), modulated DSC, powder X-ray diffraction and Fourier transformation infrared spectroscopy. The dissolution of all the ternary solid dispersions was tested in vitro under non-sink conditions. All the prepared solid dispersions were amorphous in nature. In FaSSIF at 25 °C, the melt-quenched (MQ) solid dispersions of EZ were more soluble than the spray-dried (SD) solid dispersions and supersaturation was maintained. However, at 37 °C, rapid and variable precipitation behavior was observed for all the MQ and SD formulations. In FaSSGF, the melting method resulted in better solubility than the spray-drying method at both temperatures. Ternary solid dispersions show potential for improving solubility and supersaturation. However, powder dissolution experiments of these solid dispersions of EZ at 25 °C may not predict the supersaturation behavior at physiologically relevant temperatures.

Improvement in the Oral Bioavailability and Efficacy of New Ezetimibe Formulations—Comparative Study of a Solid Dispersion and Different Micellar Systems

“…These results confirmed an increase in the amorphous form of EZ present in SD which improves solubility. Similar increases in the solubility of poorly soluble drugs have been observed with various hydrophilic cellulose polymers [ 13 , 16 ].…”

“…The high solubility results observed with the highest surfactant ratios in MS-I (1:0.75) and MS-II (1:0.75) indicated a more rapid micelle formation process at this pH [ 17 ]. The differences between the formulations with ratios 1:0.25, 1:0.5 and 1:0.75 may be related to an improvement in the interaction of the surfactant with the croscarmellose chains and ezetimibe particles, MS-I (1:0.25) may present a slower micelle formation process and increase EZ precipitation, thus reducing its solubility values [ 16 ]. The microscopic study of the residual solids of these formulations at the end of the solubility showed significant decrease ( p < 0.05) in EZ crystalline precipitate with a lower amount of agglomerated particles for MS-I (1:0.75) and MS-II (1:0.75) compared to MS-I (1:0.25) and MS-II (1:0.25).…”

Self-Micellizing Technology Improves the Properties of Ezetimibe and Increases Its Effect on Hyperlipidemic Rats

“…These results match with the amorphous form of EZ observed in the PXRD and support the presence of a film on the carrier surface in SEM studies. This surfactant film and the decrease in croscarmellose crystallization could improve the wettability of these micellar systems and decrease the EZ aggregation process during dissolution studies [4,27]. Figure 4 shows the dissolution profiles of EZ-RM, physical mixture (PM), and the micellar systems MS-K (1:0.1), MS-K (1:0.3), MS-K (1:0.6), and MS-K (1:0.75).…”

Silodosin oral films: Development, physico-mechanical properties and in vitro dissolution studies in simulated saliva

“…This may be because the increase in polymer concentration led to the formation of a gel-like state which decreased water uptake and retarded drug release, as reported by Singh and Harmanpreet [50]. Alhayali et al have previously reported that, in some cases of solid drug dispersions, the drug concentrations do not change with different drug:polymer ratios [51]. Addition of TPGS also improved the drug release noticeably.…”