Ultrasound-stimulated Brownian ratchet enhances diffusion of molecules retained in hydrogels.

We demonstrate that low-frequency ultrasonic stimulation applied directly to a hydrogel, at energy levels below the cavitation threshold, can control the release of a therapeutic molecule. The hydrogel that contained the molecules was enclosed within a hollow acoustic horn. The harmonic modes in the acoustic horn combined with the physical gel structure to induce a flashing ratchet that released all of the retained molecules in less than 90 s at an intensity of 1.5 W cm-2 (applied energy of 135 J cm-2, ultrasound center frequency of 27.9 ±â€¯1.5 kHz). In contrast, ultrasound is used currently as a remote stimulus for drug-delivery systems, at energy levels above the cavitation threshold. The low-energy flashing ratchet approach that we describe is applicable to drive the diffusion of molecules in a range of gels that are ubiquitous in biomedical systems, including for example in drug delivery, molecule identification and separation systems.

Prediction of the onset of crystallization of amorphous sucrose below the calorimetric glass transition temperature from correlations with mobility.

The objective of the present work is to determine if crystallization onset observed for an amorphous solid correlate with relaxation time at temperatures above and below the calorimetric glass transition (T(g)). Crystallization onset of spray-dried and freeze-dried amorphous sucrose were measured calorimetrically. Relaxation times measured in two temperature ranges by different techniques (isothermal calorimetry, dielectric spectroscopy) followed the expected modified Vogel-Tammann-Fulcher (VTF) behavior when extrapolated to a temperature near T(g). However, the change in slope was more conspicuous for freeze-dried sucrose, indicating that amorphous materials generated using different techniques differ in their mobilities for temperatures below T(g). Dielectric relaxation time values obtained above T(g) were well correlated to onset of crystallization. The model predicted 21 days for crystallization onset for spray-dried samples stored 7 K below T(g), compared to the experimentally observed crystallization onset of 17 days. Onset times versus temperature for freeze-dried sucrose, however, show a change in slope on approaching T(g), with the onsets somewhat decoupling from measured mobility for temperatures below T(g). Molecular mobility in amorphous materials at temperatures both above and below T(g) can be correlated to macroscopic physical change such as crystallization, but prediction of crystallization onset from relaxation time is only qualitatively correct at temperatures well below T(g).

Limitations of amorphous content quantification by isothermal calorimetry using saturated salt solutions to control relative humidity: alternative methods.

Despite the high sensitivity of isothermal calorimetry (IC), reported measurements of amorphous content by this technique show significant variability even for the same compound. An investigation into the reasons behind such variability is presented using amorphous lactose and salbutamol sulfate as model compounds. An analysis was carried out on the heat evolved as a result of the exchange of water vapor between the solid sample during crystallization and the saline solution reservoir. The use of saturated salt solutions as means of control of the vapor pressure of water within sealed ampoules bears inherent limitations that lead in turn to the variability associated with the IC technique. We present an alternative IC method, based on an open cell configuration that effectively addresses the limitations encountered with the sealed ampoule system. The proposed approach yields an integral whose value is proportional to the amorphous content in the sample, thus enabling reliable and consistent quantifications.

The effect of dehydration conditions on the functionality of anhydrous amorphous raffinose.

The purpose of this investigation is to study the effect of dehydration conditions of raffinose pentahydrate (RF.5H2O) on the physical properties and functionality of the resulting material. Crystalline RF.5H2O was dehydrated at two temperatures, 80 degrees C and 110 degrees C, producing the amorphous anhydrous form (RF.am). The dehydration temperature had no effect on a number of physical properties of the obtained RF.am, including X-ray powder diffraction, surface energy and water uptake. However, despite resulting on the same dynamics and extent of water sorption, different dehydration temperatures produced amorphous samples with drastically different recrystallization tendencies. Thermodynamic parameters show that despite the similarities on certain physical attributes, different dehydration temperature results in samples with significantly different free energy, hence stability. The difference in free energy produced by the dehydration temperature is attributed to differences in supramolecular structure that persist even in the liquid domain (above T(g)) of the amorphous samples. Evidence of such effects is observed as fluctuations in heat capacity present in RF.am but absent in the freshly prepared glass and also supported by the presence of molecular mobility modes observed using thermal polarization measurements.

Microcalorimetric measurement of the interactions between water vapor and amorphous pharmaceutical solids.

PURPOSE: Use a microcalorimetric technique to measure the interactions between water vapor and amorphous pharmaceutical solids and describe the relationship between long-term physical stability and the storage relative humidity (RH) at constant temperature. METHODS: A thermal activity monitor was used to characterize interactions of water vapor with spray-dried amorphous sucrose, lactose, raffinose, and sodium indomethacin. Differential scanning calorimetry was used to measure glass transition temperature, Tg. X-ray powder diffraction was used to confirm that the spray-dried samples were amorphous. Scanning electron microscopy was used to examine particle morphology. Specific surface area was determined by BET analysis of nitrogen and krypton adsorption isotherms. RESULTS: The moisture-induced thermal activity traces (MITATs) of the materials in this study exhibit general behavior that helps explain the effect of moisture content on the physical stability of the glassy phase at a given storage temperature. At some RH threshold, RHm, the MITAT exhibits a dramatic increase in the energy of interaction between water vapor and the glass that cannot be explained by a phase or morphology change. Calorimetric data indicate that water vapor-solid interactions are reversible below RHm; above RHm, energetic hysteresis is observed and water-water interactions predominate. In addition, the MITAT was deconvoluted into sorptive and nonsorptive components, making it possible to assign the observed heat flow to unique thermal events. Samples stored at a RH just below RHm for more than 2 months show no evidence of morphology or phase change. In addition, the MITAT can be deconvoluted into sorptive and nonsorptive components by using a twin-calorimeter arrangement. This analysis provides specificity to the microcalorimetric analysis and helps explain the nature of the physical changes that occur during the hydration glassy phase. CONCLUSIONS: The MITAT is a useful tool to determine the onset of moisture-induced physical instability of glassy pharmaceuticals and may find a broad application to determine appropriate storage conditions to ensure long-term physical stability.