Lyophilization/Freeze Drying of Mannitol vs Pure Water (time-lapse of 20 hour process)
Channel: LyoHUB
Date: 2020-09-21

Freeze-drying of  5% w/v mannitol (vial on the left) and pure water (vial on the right) in pharmaceutical vials (size 6R) at 3 ml fill.  The product temperature is monitored by a thermocouple in the mannitol vial.  SEE KEY MOMENTS below. Process recipe: 
* Cooling for 3.5 hours at 0.3 deg/min from 20C to -45 C
* Freezing at -45 C for 2.5 hours
* Primary drying at 60 mtorr, Tsh=20 C for 12 hr.

01:14 - Ice Nucleation and Freezing: (real time: 2h:2m:4s) Ice nucleates in pure water in less than a sec, Tsh= -18 C, Tpr=-2.2 C.  (real time: 2h:4m) - Ice nucleation in Mannitol starts and takes about 5 sec, Tsh=-18.6 C, Tpr=-2.8 C.  

01:35 - Freezing completes in pure water and "volcano" forms. (real time: 2h:19m) -    Freezing front propagates half-way from the bottom up. Tsh=-23 C, Tpr=-8 C.  (real time: 2 hr 35: min) - Freezing completes in pure water, Tsh=-28 C, Tpr=-22 C.  “Volcano formation” is clearly seen due to expansion of ice and inward radial freezing. See  “Lyophilized Drug Product Cake Appearance: What Is Acceptable?”, Patel et al, JPharmSci (2017) 106:1706-1721. (real time: 2h:38m) -   Freezing completed in Mannitol solution, Tsh=-29 C, -23 C. 

04:20 - Primary drying at vacuum pressure of 60 mtorr and shelf temperature Tsh=+20 C.  (real time: 06h:42m)  Vacuum onset, the primary drying starts, Tpr=-41 C.  

06:35 - Primary drying completion at about 50%  for water sample. (real time: 10h:20m:00s)   About  50% of ice remains for pure water sample,  mannitol temperature increases toTpr=-19 C.

08:15 - Completion of drying after about 13 hours. The mannitol vial "lifts off" and only a small ball of ice remains in the water vial.