Optimization of Freeze-Drying Cycles Using

Modulated Differential Scanning

Calorimetry (MDSC®)

Steven R. Aubuchon, Ph.D.

Product Manager, Thermal Analysis
saubuchon@tainstruments.com
Background on Freeze-drying Process
Stages of Freeze-drying:
1. Freezing
• Vials Cooled to –10 to –45°C
• Converts Most Water to Ice
• Concentrates Solute in Vial
2. Primary Drying
• Ice Sublimation and Removal Under Vacuum
• Time Varies from 5 Hours to More Than 5 Days
• Knowledge of Glass Transition Temperature is
Critical to Prevent Collapse of “Cake”
3. Secondary Drying
• Evaporation/Desorption of Unfrozen Water
• Temperature can be Increased to Reduce Time But
Needs to be Kept Below Glass Transition
(Collapse) Temperature
Background on Freeze-drying Process

ƒ The bulking agent, which can be either crystalline or

amorphous, and its interaction with frozen and
unfrozen water in the frozen solution, define the
physical structure which is essential to successful
freeze-drying.
ƒThis structure manifests itself in the form of
transitions that occur at specific temperatures.
ƒKnowledge of how the structure changes with time
and temperature is critical
ƒThe flow characteristics (viscosity) of an
amorphous bulking agent change by several
orders of magnitude over just a few °C in the
temperature region of the glass transition
ƒThis can dramatically affect drying time!!
 Background on Freeze-drying Process

The ability to accurately measure Tg in the frozen

solution or in the partially and fully fried lyophilized
cakes greatly improves the cost effectiveness and
the quality of the final product.
• Cake collapse should not occur at temperatures
below Tg
• For efficiency, the process should be run at the
highest possible temperature
–The rate of sublimation (primary drying) approx.
doubles with an increase of just a 5°C* in
process temperature
*M.J. Pikal, Course notes on Freeze-Drying
State Diagram on Sucrose-Water Solutions
 Why Use Modulated DSC®?

MDSC® is the preferred analytical technique

because:
• MDSC is much more sensitive at the low
heating rates required for accurate
temperature measurements
• MDSC can separate overlapping transitions
to greatly simplify interpretation of the data
• MDSC has the unique ability to measure
heat capacity under isothermal conditions
–Extremely useful for following changes in
structure or sublimation rate as a function
of time and temperature
Q2000 Modulated DSC System
 Typical DSC Transitions

Oxidation
Or
Crystallization Decomposition
Heat Flow → exothermic

Melting
Glass
Cross-Linking
Transition
(Cure)

Composite graph

Temperature
Standard DSC of Frozen Sucrose Solution
MDSC® of Frozen Sucrose Solution

Note: Heating
Rate 0.5C/min
Structural Comparison of Frozen Sucrose
Solution During Slow Cooling and Heating
 Understanding Structural Differences Between
Quenched and Slow-Cooled Sucrose-Water Solution

5 0.2

Shape of Derivative Due to

Water Freezing with Peak at -36°C
0.1

Quench Cooled
4

Deriv. Rev Cp (J/g/°C/min)

0.0
Derivative Signals
Slow Cooled
Rev Cp (J/g/°C)

3 -0.1
Quench Cooled

-0.2

2
Slow Cooled
Heat Capacity Signals
-0.3
Both Steps Due to Tg
Amorphous Sucrose
1 -0.4
-60 -50 -40 -30 -20
Temperature (°C) Universal V3.8A TA Instruments
One Experiment on Same Sample Shows Metastability of
Quench-cooled 40% Sucrose-water Solution
Measuring Time-Dependence of Processes
with Modulated Differential Scanning
Calorimetry (MDSC®)
 Question:
Is the Structure of a Slow Cooled
Frozen Solution Stable?

NO !
10% Sucrose-water Solution in Open DSC Hermetic Lid
(Permits Sublimation of Water)

Sample in Hermetic Lid

Effect of 20 Hours of Drying at -40°C on Structure
of 10% Sucrose-water Solution
 Question:
Can MDSC Measure the Rate of
Sublimation at -40°C ?

YES !
Use of MDSC to Study Sublimation (Drying) Rate

During the process of drying @ -40°C;

• The amount of water in the sample is decreasing
• The sample’s heat capacity is decreasing because
ice has a relatively high heat capacity of ≈ 2 J/g°C
–MDSC has very high sensitivity to measure heat
capacity or changes in heat capacity
• The structure of the sample is changing, especially
the structure associated with transitions below -40°C
–Molecular mobility increases significantly at
temperatures above a glass transition.
ƒAt -40°C, the sample is above the first step in
heat capacity
Drying Temperature is Chosen Just Above the Tg

Quenched
Slow‐cooled
Drying Temperature

Liquid (Mobile) 
Phase

Glassy (Rigid) Phase
Heat Capacity of Solution Decreases During Drying
Due to Both Structure Change and Mass Loss

Tg
Heat Capacity of Solution Decreases During Drying
Due to Both Structure Change and Mass Loss

Tg
Heat Capacity of Solution Decreases During Drying
Due to Both Structure Change and Mass Loss

Tg
Heat Capacity of Dilute Solution Decreases During
Drying Due Only to Mass Loss
 MDSC Relative Drying Rates of
Sucrose/Water Solutions at -40°C

Once structural changes stop or reach an insignificant rate,

the decrease in heat capacity with time is a relative measure
of drying rate.

Rate of Cp Drying Rate Relative

Concentration Time to Tg (h) Decrease to 10%
J/g°C/h (x 10-4 ) Concentration
10% 6.5 7.8 1
7.5% 5 11.1 1.4
5.0% 4 41.6 5.4
2.5% N/A 50.6 6.6
 Characterization of Lyophilized Samples

ƒAmorphous structure is easily plasticized by

water and other solvents. As little as 2-3%
water can lower Tg by up to 100°C
ƒTo measure an accurate Tg in a sample with
a volatile component, it is necessary to
maintain the volatile content by running the
sample in a hermetic (sealed) pan
ƒUse a dry-box or dry-bag to prepare samples
in hermetic pans. This eliminates water
absorption during preparation and loss of
water during the measurement
Absorbed Moisture Acts as a Plasticizer
to Lower the Tg of Sucrose
Implications for storage conditions

Tg of Dry Sucrose ≈ 68°C

 Conclusions

ƒ The success of a freeze-drying cycle is highly

dependant on choosing the proper conditions
ƒDrying Temperatures
ƒDrying Times
ƒ Modulated DSC® is a primary tool in characterizing the
freeze-concentrated solution, which gives precise
information regarding lyophilization conditions
ƒModulated DSC can measure both the temperature-
dependant and time-dependant processes which
occur in frozen solutions
ƒ Modulated DSC is useful in the characterization of
lyophilized materials
ƒImplications for storage stability
 Any Questions?

Steven Aubuchon
Product Manager, Thermal Analysis
saubuchon@tainstruments.com
+1 302.427.4073