Physical Stability of the Amorphous Anticholesterol Agent (Ezetimibe): The Role of Molecular Mobility

Abstract

The purpose of this paper is to examine the role of molecular mobility in the recrystallization process from the amorphous state of the anticholesterol drug ezetimibe. Both the molecular dynamics and crystallization kinetics have been studied using various experimental techniques, such as broadband dielectric spectroscopy (BDS), differential scanning calorimetry (DSC), and X-ray diffraction (XRD). Our investigations have shown that ezetimibe easily recrystallizes from the disordered state, both below and above its glass transition temperature (Tg = 336 K). Moreover, we found that an only slightly elevated pressure (5 MPa) significantly accelerates the recrystallization process at T > Tg. We predict that the structural relaxation time of amorphous ezetimibe at 293 K (storage temperature) and ambient pressure is only 22 days. This result corresponds to the characteristic time, determined from XRD measurements, for amorphous ezetimibe to recrystallize during storage at Troom = 298 K. It leads to the conclusion that the molecular mobility reflected in structural relaxation of ezetimibe is mainly responsible for devitrification of this drug. Finally, we determined a relatively easy way to improve the physical stability of the drug by preparing a binary amorphous ezetimibe-Soluplus mixture. Ezetimibe in an amorphous mixture with 20 wt % Soluplus has a much better (over six times) solubility than the pure crystalline material.

Polymeric Amorphous Solid Dispersions: A Review of Amorphization, Crystallization, Stabilization, Solid-State Characterization, and Aqueous Solubilization of Biopharmaceutical Classification System Class II Drugs

“…Knapik et al have shown that the physical stability and water solubility of the amorphous drug (ezetimibe) were improved over 6 times when mixed within a PASD using Soluplus® as carrier. 125 DSC and dielectric spectroscopy analysis of amorphous ezetimibe have led to the conclusion that the high molecular mobility, reflected in structural relaxation, is mainly responsible for its high crystallization tendency. This indicates that formation of a PASD in the Sol-uplus® matrix acts as physical barrier to the molecular motions of glass ezetimibe leading to improved stability.…”

Molecular Dynamics and Physical Stability of Amorphous Nimesulide Drug and Its Binary Drug–Polymer Systems

“…Similar behavior was previously observed in the case of ezetimibe, celecoxib and sildenafil. 20,21,22,23 Figure 1 presents dielectric spectra collected at temperatures below T g . In this temperature region the structural relaxation becomes too slow to be observed and only secondary relaxation processes may be visible.…”

Mechanistic Study of Belinostat Oral Absorption From Spray-Dried Dispersions

“…Molecular mobility is a key attribute for maintaining physical stability. 15,20,21 In addition, some polymers have the ability to stabilize supersaturated aqueous drug concentrations, resulting in higher absorption potential (i.e., drug activity) relative to the crystalline form. 22,23 The maximum supersaturated concentration achievable is a function of the drug properties (i.e., chemical potential of the solid form) 24 and is represented in solution by the point at which amorphous phase separation occurs, termed liquid-liquid phase separation (LLPS).…”