optimization of freeze drying

8/7/2019 Optimization of Freeze Drying

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Optimization of Freeze-Drying Cycles UsingModulated Differential Scanning

Calorimetry (MDSC

)

Steven R. Aubuchon, Ph.D.

Product Manager, Thermal Analysis

[email protected]


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Background on Freeze-drying Process

Stages of Freeze-drying:1.

Freezing

Vials Cooled to 10 to 45C

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 ofGlass Transition Temperature isCritical 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


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The bulking agent, which can be either crystalline oramorphous, and its interaction with frozen andunfrozen water in the frozen solution, define the

physical structure which is essential to successfulfreeze-drying.

This structure manifests itself in the form of

transitions that occur at specific temperatures.Knowledge of how the structure changes with timeand temperature is critical

The flow characteristics (viscosity) of anamorphous bulking agent change by severalorders of magnitude over just a few C in thetemperature region of the glass transition

This can dramatically affect drying time!!


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The ability to accurately measure Tg in the frozensolution or in the partially and fully fried lyophilizedcakes greatly improves the cost effectiveness and

the quality of the final product. Cake collapse should not occur at temperaturesbelow Tg For efficiency, the process should be run at thehighest possible temperature The rate of sublimation (primary drying) approx.doubles with an increase of just a 5C* inprocess temperature

*M.J. Pikal, Course notes on Freeze-Drying


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State Diagram on Sucrose-Water Solutions


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Why Use Modulated DSC?

MDSC

is the preferred analytical technique

because:

MDSC is much more sensitive at the lowheating rates required for accuratetemperature measurements

MDSC can separate overlapping transitionsto greatly simplify interpretation of the data

MDSC has the unique ability to measure

heat capacity under isothermal conditions Extremely useful for following changes instructure or sublimation rate as a function

of time and temperature


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Q2000 Modulated DSC System


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Typical DSC Transitions

Temperature

HeatFlow

exothermic

Glass

Transition

Crystallization

Melting

Cross-Linking

(Cure)

Oxidation

Or

Decomposition

Composite graph


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Standard DSC of Frozen Sucrose Solution


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MDSCof Frozen Sucrose Solution

Note: Heating

Rate 0.5C/min

S l C i f F S


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Structural Comparison of Frozen SucroseSolution During Slow Cooling and Heating


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Understanding Structural Differences BetweenQuenched and Slow-Cooled Sucrose-Water Solution

Shape of Derivative Due toWater Freezing with Peak at -36C

Quench Cooled

Quench Cooled

Slow Cooled

Slow Cooled

Heat Capacity Signals

Derivative Signals

-0.4

-0.3

-0.2

-0.1

0.0

0.1

0.2

Deriv.

RevC

p(J/g/C/min)

1

2

3

4

5

RevCp

(J/g/C)

-60 -50 -40 -30 -20

Temperature (C) Universal V3.8A TA Instruments

Both Steps Due to Tg

Amorphous Sucrose


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One Experiment on Same Sample Shows Metastability ofQuench-cooled 40% Sucrose-water Solution


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Measuring Time-Dependence of Processeswith Modulated Differential Scanning

Calorimetry (MDSC

)


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Question:Is the Structure of a Slow Cooled

Frozen Solution Stable?

NO !

10% Sucrose water Solution in Open DSC Hermetic Lid


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10% Sucrose-water Solution in Open DSC Hermetic Lid(Permits Sublimation of Water)

Sample in Hermetic Lid

Eff f 20 H f D i 0 C S


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Effect of 20 Hours of Drying at -40C on Structureof 10% Sucrose-water Solution


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Question:Can MDSC Measure the Rate of

Sublimation at -40C ?

YES !


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Use of MDSC to Study Sublimation (Drying) Rate

During the process of drying @ -40C;

The amount of water in the sample is decreasing

The samples heat capacity is decreasing becauseice has a relatively high heat capacity of 2 J/gC

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 -40C

Molecular mobility increases significantly attemperatures above a glass transition.At -40C, the sample is above the first step in

heat capacity


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Drying Temperature is Chosen Just Above the Tg

Quenched

DryingTemperatureSlowcooled

Glassy(Rigid)Phase

Liquid(Mobile)

Phase

Heat Capacit of Sol tion Decreases D ring Dr ing


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Heat Capacity of Solution Decreases During DryingDue to Both Structure Change and Mass Loss

Tg

H C i f S l i D D i D i


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Tg

H t C it f S l ti D D i D i


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Tg


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MDSC Relative Drying Rates of


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MDSC Relative Drying Rates ofSucrose/Water Solutions at -40C

Once structural changes stop or reach an insignificant rate,

the decrease in heat capacity with time is a relative measure

of drying rate.

Concentration Time to Tg (h)

Rate of Cp

Decrease

J/gC/h (x 10-4 )

Drying Rate Relative

to 10%

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


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Characterization of Lyophilized Samples

Amorphous structure is easily plasticized by

water and other solvents. As little as 2-3%

water can lower Tg by up to 100CTo 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

Use a dry-box or dry-bag to prepare samplesin hermetic pans. This eliminates water

absorption during preparation and loss of

water during the measurement

Absorbed Moisture Acts as a Plasticizer


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Absorbed Moisture Acts as a Plasticizerto Lower the Tg of Sucrose

Tg of Dry Sucrose

68C

Implications for storage conditions


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Any Questions?

Steven Aubuchon

Product Manager, Thermal Analysis

[email protected]+1 302.427.4073
mailto:[email protected]:[email protected]

optimization of freeze drying

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