The application of low field nuclear magnetic resonance as a materials characterization tool in pharmaceutical freeze -drying

The broad objective of the presented research is to develop a more analytical basis for formulation and process development of freeze-drying in order to minimize trial and error experimentation. First, the feasibility of using magnetic resonance imaging (MRI) to observe the time course of the shape and position of the sublimation front moving profile during primary freeze-drying were investigated. It was found that the ice sublimation front can be observed with the help of 0.1 mM hydrobromic acid (HBr) as a dopant and using a single point ramped imaging with T1 enhancement (SPRITE) sequence. The shape of the sublimation front estimated through the temperature profile study by thermocouples agreed with the MRI observations. The sublimation front obtained experimentally is much more curved than those predicted by published models of heat and mass transfer in freeze-drying. These models appear to underestimate lateral heat transfer in vials. It was also found that residual moisture distribution in a freeze-dried HSA with as high as 11% moisture cannot be measured in this study. A high field NMR instrument and a stronger gradient may decrease the detection limit. Second, composition and temperature dependences of glycine crystallization rate during annealing from a glycine/sucrose excipient systems were examined using nuclear magnetic resonance (NMR) as well as differential scanning calorimetric (DSC). It was found that half crystallization time were similar as measured by NMR and DSC. However, the NMR method is significantly more sensitive. A linear relationship was observed between the logarithm of the half crystallization time and the logarithm of the molar ratio of glycine and the temperature dependence of the crystallization rate followed an Arrhenius relationship. Third, both polymers and disaccharide systems were examined by NMR and DSC in order to further understand the physical significance of the molecular mobility change temperature in amorphous systems. Results from this study suggest: (1) the appearance of a second Lorenzian decay is not a reliable indication for molecular mobility change temperature for freeze-dried samples at pharmaceutically relevant residual moisture levels; (2) Tg as measured by DSC is a good indicator of the molecular mobility change temperature in small molecules; (3) NMR is more sensitive to the molecular mobility change within the polymer systems than DSC