Rapid assessment of the structural relaxation behavior of amorphous pharmaceutical solids: effect of residual water on molecular mobility.
OBJECTIVE
Use RH-perfusion microcalorimetry and other analytical techniques to measure the interactions between water vapor and amorphous pharmaceutical solids; use these measurements and a mathematical model to provide a mechanistic understanding of observed calorimetric events.


METHODS
Isothermal microcalorimetry was used to characterize interactions of water vapor with a model amorphous system, spray-dried raffinose. Differential scanning calorimetry was used to measure glass transition temperature, T (g). High-sensitivity differential scanning calorimetry was used to measure enthalpy relaxation. X-ray powder diffraction (XRPD) was used to confirm that the spray-dried samples were amorphous. Scanning electron microscopy (SEM) was used to examine particle morphology. Gravimetric vapor sorption was used to measure moisture sorption isotherms. Thermogravimetric analysis (TGA) was used to measure loss on drying.


RESULTS
A moisture-induced thermal activity trace (MITAT) provides a rapid measure of the dependence of molecular mobility on moisture content at a given storage temperature. At some relative humidity threshold, RH(m), the MITAT exhibits a dramatic increase in the calorimetric rate of heat flux. Simulations using calorimetric data indicate that this thermal event is a consequence of enthalpy relaxation.


CONCLUSIONS
RH-perfusion microcalorimetry is a useful tool to determine the onset of moisture-induced physical instability of glassy pharmaceuticals and could find a broad application to determine appropriate storage conditions to ensure long-term physical stability. Remarkably, thermal events measured on practical laboratory timescales (hours to days) are relevant to the stability of amorphous materials on much longer, pharmaceutically relevant timescales (years). The mechanistic understanding of these observations in terms of enthalpy relaxation has added further value to the use of RH-perfusion calorimetry as a rapid means to characterize the molecular mobility of amorphous solids.
Miller
Danforth P
DP
Nektar Therapeutics, 150 Industrial Road, San Carlos, California 94070, USA. dmiller@nektar.com
Lechuga-Ballesteros
David
D
D000327:Adsorption; D000465:Algorithms; D002152:Calorimetry, Differential Scanning; D004356:Drug Storage; D005612:Freeze Drying; D006813:Humidity; D008855:Microscopy, Electron, Scanning; D015233:Models, Statistical; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011208:Powders; D011887:Raffinose / Q000737:chemistry; D013696:Temperature; D013818:Thermogravimetry; D014867:Water; D014961:X-Ray Diffraction
D004364:Pharmaceutical Preparations; D011208:Powders; D014867:Water; D011887:Raffinose