Atorvastatin as a Promising Crystallization Inhibitor of Amorphous Probucol: Dielectric Studies at Ambient and Elevated Pressure

Abstract

The aim of this article was to check the physical stability of the amorphous form of probucol at both standard storage and manufacturing conditions. Our studies clearly show that disordered form of the examined, cholesterol lowering, agent stored at ambient pressure does not reveal any tendency toward recrystallization. The physical stability of neat probucol stored at ambient pressure has been investigated (i) at room temperature by means of X-ray diffraction technique (XRD) as well as (ii) at T = 333 K by means of broadband dielectric spectroscopy (BDS). Due to the fact that compression is an important stage of drugs manufacturing we additionally performed physical stability tests of amorphous probucol at elevated pressure. The recrystallization tendency of the examined pharmaceutical has been tracked online from the initial and further up to a few hours after compression by means of the high pressure BDS technique. These experiments indicate that even very small pressure applied during the sample compression immediately induce its recrystallization. Since, the sensitivity on pressure eliminates probucol from the group of physically stable amorphous APIs, its stabilization is required. Taking into account that there are many scientific reports describing the positive effect of coadministration of probucol with the drug atorvastatin, we used the latter as probucol's crystallization inhibitor.

Enhancement of the Physical Stability of Amorphous Sildenafil in a Binary Mixture, with either a Plasticizing or Antiplasticizing Compound

“…Successful stabilizers can be categorized into two groups. Stabilizers of the first category, consisting of low molecular weight compounds such as: acetylated sugars [9,13], organic acids [14][15][16], or even different drugs [17][18][19][20][21][22], have proved to be very effective in inhibiting recrystallization. However, the vast majority of stabilizers are large molecular weight compounds (the second group), such as polymers [5,7,[23][24][25][26][27][28].…”

Physical Stability and Viscoelastic Properties of Co-Amorphous Ezetimibe/Simvastatin System

“…In the literature, one can find a lot of examples indicating that amorphization remarkably improves the water solubility and bioavailability of poorly soluble drugs [21,22,23,24,25]. It has to be noted that amorphous APIs have unfortunately one disadvantage, which blocks their widespread use [26,27,28,29,30]. Mainly, these APIs are physically unstable.…”

Advances in coamorphous drug delivery systems

“…. For instance, in the study of physical stability of amorphous probucol in the presence and absence of atorvastatin, the progress of isothermal crystallization is monitored and analyzed in terms of the normalized real permittivity 61 .…”

“…Recently, the change of real parts of the complex dielectric permittivity obtained from broadband dielectric spectroscopy can be used to characterize the crystallization of amorphous formulations to a certain extent59., 60.. For instance, in the study of physical stability of amorphous probucol in the presence and absence of atorvastatin, the progress of isothermal crystallization is monitored and analyzed in terms of the normalized real permittivity 61 .…”