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

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 \u3c TAM \u3c 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.

Heat and mass transfer scale-up issues during freeze drying: II. Control and characterization of the degree of supercooling

This study aims to investigate the effect of the ice nucleation temperature on the primary drying process using an ice fog technique for temperature-controlled nucleation. In order to facilitate scale up of the freeze-drying process, this research seeks to find a correlation of the product resistance and the degree of supercooling with the specific surface area of the product. Freeze-drying experiments were performed using 5% wt/vol solutions of sucrose, dextran, hydroxyethyl starch (HES), and mannitol. Temperature-controlled nucleation was achieved using the ice fog technique where cold nitrogen gas was introduced into the chamber to form an “ice fog”, there-by facilitating nucleation of samples at the temperature of interest. Manometric temperature measurement (MTM) was used during primary drying to evaluate the product resistance as a function of cake thickness. Specific surface areas (SSA) of the freeze-dried cakes were determined. The ice fog technique was refined to successfully control the ice nucleation temperature of solutions within 1°C. A significant increase in product resistance was produced by a decrease in nucleation temperature. The SSA was found to increase with decreasing nucleation temperature, and the product resistance increased with increasing SSA. The ice fog technique can be refined into a viable method for nucleation temperature control. The SSA of the product correlates well with the degree of supercooling and with the resistance of the product to mass transfer (ie, flow of water vapor through the dry layer). Using this correlation and SSA measurements, one could predict scaleup drying differences and accordingly alter the freeze-drying process so as to bring about equivalence of product temperature history during lyophilization