Title

Stability of amorphous pharmaceuticals: Prediction of onset of crystallization using experimental relaxation times

Date of Completion

January 2007

Keywords

Health Sciences, Pharmacology

Degree

Ph.D.

Abstract

Formulation of new drug candidates is becoming increasingly difficult due to the low solubility associated with them. In such cases, the amorphous state is extremely appealing. However, the biggest obstacle in successful use of the amorphous state is its unpredictable physical stability or the tendency to revert to more stable crystalline state that precludes the use of amorphous state in commercial solid oral dosage forms. Instability in amorphous matrices, particularly physical instability or crystallization from amorphous state, has often been linked to the molecular mobility of these systems. The objective of this research was to better understand the correlation between molecular mobility in the amorphous matrix and onset of crystallization and to use this understanding to perhaps develop a stability testing protocol for crystallization from the amorphous state. Development of any stability protocol from correlations with molecular mobility require validating the two assumptions; (a) the relaxation times measured at temperatures above and below the glass transition using different techniques are the same or are at least highly coupled and (b) there is a good coupling between crystallization onset time and relaxation times at the measurement temperatures above the glass transition temperature.^ Molecular mobility in the amorphous matrix was determined over a broad temperature range from temperatures above the glass transition (Tg) to temperatures below the glass transition temperature. Dielectric relaxation spectroscopy was used to determine the relaxation time constants above the Tg. Calorimetric techniques (MDSC and TAM) and Thermally Stimulated Depolarization Current Spectroscopy (TSDC) were used to measure relaxation dynamics below the Tg. It was shown that all measures of molecular mobility below the Tg, though divergent at lower temperatures, extrapolated to the relaxation times measured above the Tg determined using dielectric spectroscopy. The results suggests that the relaxation times measured below the glass transition temperature are dependent on the technique used to measure the molecular mobility and followed the trend TSDC < TAM < MDSC (τ).^ Onset times to crystallization were coupled with dielectric relaxation times in the above Tg temperature range for all compounds (indomethacin, felodipine and flopropione) except nifedipine. Good quantitative agreement between predicted and experimental crystallization onset times was obtained for two compounds (indomethacin and flopropione) at two temperature points below Tg. Crystallization growth rates also coupled with the measured dielectric relaxation times. Though the above protocol may be used as a first step in developing the stability testing protocol for crystallization from amorphous state, clearly compound specific characteristics and critical processing conditions play a significant role in successful use of the protocol. ^