1、冻干显微镜下的冻干工艺 GoodOKPoorPoorThe product in the “Poor” vials has become soft and dense during freeze-drying, because it has become warmer than its “Critical Temperature”!Sample holderSide DoorBlock Sample loading takes about 60 seconds. Routine analysis usually takes 30 90 minutesTemperature-Controlled
2、 BlockLight Source (from below)ApertureQuartz cover slip (16 mm dia.)Glass cover slip (13 mm dia.)2l of sampleObjective Lens (usually 10 x)Metal Spacer (70m thick)Frozen sampleDried sampleSublimation frontOn-line plotTemp/time tableINITIAL FDM IMAGEFrozen sampleSublimation frontCollapsed materialINT
3、ERPRETATION OF EVENTSFrozen sampleCollapsed sampleRegained structure Sublimation frontINTERPRETATION OF EVENTSDried sample with structureCollapsing again on reheatingFrozen sampleSublimation frontINTERPRETATION OF EVENTSBelow Tc of amorphous phaseAbove Tc of amorphous phaseA similar effect may also
4、be observed due to the melting of crystalline component(s) onto a rigid amorphous structure (depending on which has the lower critical temperature)Macroscopically similar but is it:Wetter?Less stable?More difficult to reconstitute?-41oC, around Tc for glucose. Possible evidence of visible micro-coll
5、apse(Drying front)Frozen materialRegions with good dried structure. Just mannitol?Regions of (micro) collapse. Just glucose?FrozenDryNote changes in appearance of frozen structureEutectic liquidLayer of concentrated solute at edge of sampleDrying only occurs through breaks in the crustSample cooled
6、to -40C, then warmed to -10CSame sample after a further 15 minutes at -10CExperiments can be carried out to compare rates of change at different temperatures, in order to establish what annealing temperature might be most efficient to use in the freeze-dryer.PolariserAnalyserSampleCameraSample quenc
7、h cooled below -40CNo sign of crystals (no light rotation)Same Sample now drying at -18CPolariser shows presence of crystals (white areas)Zsin impedance probeSymmetry-balanced heating built into sample holding block, to give smooth baselineDTA assemblySample format for Lyotherm2 analysisSamples were
8、 cooled to below -100C and analysed on rewarmingEarly indications are that such a correlation does exist, and the extent to which each aspect of the final product is affected depends on the nature of the productSample dries well at -50.0C, but collapse starts as the temperature is increased to -45.7
9、C. This can be identified by defects appearing in the dried materialAs the temperature increases to -39.6C the structure continues to weaken and collapse becomes more evidentThe sample is repeated but this time with an annealing step frozen and cooled to -50.0C, warmed to -15.0C and re-cooled to -50
10、.0C before drying. The sample dries with good structure until the temperature reaches -31.4C and defects appearAt -30.8C the sample is too weak to maintain any structure as the ice is removed1234See full labels 1 4 on next slideTc = -45.7C+20C-15C-50C-40CShelf TemperatureProduct TemperatureChamber P
11、ressure 1231 Freezing 2 Primary Drying 3 Secondary Drying AA Product at risk of collapse+20C-15C-50C-35CShelf TemperatureProduct TemperatureChamber Pressure 1234Tc = -31.4C1 Freezing 2 Annealing 3 Primary Drying 4 Secondary DryingThis graph shows an enlarged section of the previous graph+20C-15C-50C
12、-35CShelf TemperatureProduct TemperatureChamber PressureTc = -31.4C1 Freezing 2 Annealing 3 Primary Drying 4 Secondary Drying3The Sublimation Cooling Effect The lowering of product temperature caused by the sublimation of iceFrom the previous run we now know:1. The extent of sublimation cooling, all
13、owing us to increase the shelf temperature / chamber pressure as high as possible whilst sublimation cooling keeps the product temperature below Tc2. When sublimation was complete in temperature-probed samples (when product temperature = shelf temperature)3. The physical appearance of the cakes prod
14、uced by the cycle4. Residual moisture was measured in the final product, in order to establish whether the extent of secondary drying was sufficientA recent study by BTL showed that using FMS in combination with KF titration may provide evidence of where the water isLighthouse FMS-1400and whether this changes over timeDoes Y-axis intercept (1.49%) indicate level of bound water? (sorry Felix!) it corresponds with there being zero pressure of free water
