Comprehensive studies on physical and chemical stability in liquid and glassy states of telmisartan (TEL): solubility advantages given by cryomilled and quenched material

Abstract

To make full use of the advantages provided by amorphous pharmaceuticals it is necessary to understand the basic factors that determine their physical and chemical stability. Molecular mobility seems to be the most important one. Unfortunately, due to the exceedingly long time scale required for molecular motion in the glassy state, direct monitoring of the structural α-relaxation time () in this temperature regime is rather difficult. A thorough investigation was carried out of the time scale of α-mobility in the glassy state of telmisartan (TEL). For this drug, global molecular mobility seems to be the most dominant factor responsible for its long-term stability. Based on some estimations obtained previously it was concluded that at room temperature, molecular mobility associated with the structural relaxation would exceed three years. To characterize the temperature behavior of structural relaxation below the glass transition temperature, T _g, a modified Adam–Gibbs approach was used. Additionally, using results of dielectric measurements, a comparative analysis was performed of the molecular dynamics of amorphous TEL prepared by cryomilling as well as obtained by quench-cooling of the melt. An X-ray diffraction analysis was also carried out to confirm the long-term stability of amorphous TEL, whereas solubility studies revealed its markedly better solubility profile than that for the crystalline form. These findings have important implications for further handling of this drug.

Keywords:

• amorphous material
• biological material
• dielectric material
• glass transition

Acknowledgements

The authors (KA, KG, KK, MP) are deeply thankful for the financial support within the framework of the project entitled “From Study of Molecular Dynamics in Amorphous Medicines at Ambient and Elevated Pressure to Novel Applications in Pharmacy”, which is operated within the Foundation for Polish Science Team Programme co financed by the EU European Regional Development Fund.