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Pharmaceutical Freeze Drying:

The Lyophilization Process

Nathaniel Milton, Ph.D.

Product Development, Eli Lilly and Co.

Outline
I. What is freeze drying? II. Reasons for freeze drying III. Steps in freeze drying
A. Freezing B. Primary Drying C. Secondary Drying

IV. Case Studies V. Pros and Cons of Freeze Drying


Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 2

I. What is Freeze Drying? Definition of Freeze Drying


To dry (as food) in a frozen state under high vacuum esp. for preservation (Webster Dictionary) ... a means of drying, achieved by freezing the wet substance and causing ice to sublime directly to vapor by exposing it to a low partial pressure of water vapor (Sterile Pharmaceutical Manufacturing - Applications for the 1990s)

Nathaniel Milton, Ph.D.

Product Development, Eli Lilly and Co.

II. Reasons for Freeze Drying?


Material chemically unstable in solution Low temperature drying process Compatible with protein pharmaceuticals The amorphous form of the drug is desirable (i.e., solubility) Low particulate contamination Compatible with aseptic/sterile processing

Nathaniel Milton, Ph.D.

Product Development, Eli Lilly and Co.

Pharmaceutical Freeze Drying Involves:


1. Dissolving the drug and excipients in a suitable solvent, generally water. 2. Sterilizing the bulk solution by passing it through a bacteria-retentive filter. 3. Filling into individual sterile containers. 4. Freezing the solution by placing the open containers on cooled shelves in a freeze drying chamber or pre-freezing in another chamber. 5. Applying Vacuum to the chamber and heating the shelves in order to sublime ice.
Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 5

Nathaniel Milton, Ph.D.

Product Development, Eli Lilly and Co.

Desired Freeze Dried Characteristics Intact cake Sufficient strength Uniform color Sufficiently dry Sufficiently porous Sterile Free of Pyrogens Free of particulate Chemically stable

Nathaniel Milton, Ph.D.

Product Development, Eli Lilly and Co.

III. Steps in Freeze Drying A. Freezing


Freezing of water into ice to produce a rigid frozen solute structure Solutes concentrate between ice crystals

B. Primary Drying
Removal of ice via sublimation Product temperature less than Collapse temperature

C. Secondary Drying
Remove adsorbed water Achieve moisture content needed for stability
Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 8

Freeze Drying Equipment Chamber Condenser


Condensing Coils

Vacuum Pump

Product Shelf

Compressor

Shelf Fluid Pump

Heat Exchanger

Heater
Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 9

Steps in Freeze Drying

40

Shelf Temperature
140

Mean Product Temperature

20

Chamber Pressure

120

Temperature (oC)

100

-20

80

-40

60

A
0 10

B
20 30 40

C
50 60

Time (Hours)

Nathaniel Milton, Ph.D.

Product Development, Eli Lilly and Co.

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Pressure (millitorr)

Freeze Drying

Temperature Time Pressure

Solution
Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co.

Powder
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A. Freezing Process
Cooling Supercooling Ice Nucleation

Crystal Growth A. Concentration of Solutes


Ionic strength Reaction rates Precipitation of Buffers - pH shifts

B.

Metastable Amorphous Solute annealling D. Crystalline / Amorphous mixture

C.

Crystallization of solute (eutectic)

Amorphous solute vitrification

Lyotropic liquid crystals

Nathaniel Milton, Ph.D.

Product Development, Eli Lilly and Co.

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Crystalline Solutes

Some solutes crystallize with ice during freezing Crystalline solutes

After Freezing (Freeze Concentrate)

Eutectic Mixture

The temperature where solute and ice both exist in a rigid crystalline state is the eutectic temperature. For example, NaCl forms a eutectic mixture containing 23.3%NaCl and melts at -21.13oC.
Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 13

Amorphous Solutes

Most solutes dont crystallize and form a random (amorphous) viscous glassy phase Amorphous solute After Freezing (Freeze Concentrate)

Glassy Mixture

In these systems the viscosity of solute phase increases until the solute is completely immobile and behaves like a glass. The temperature where the solute behavior changes from solution to a rigid glass is the glass transition temperature.
Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 14

Physical State of the Solute and Temperature: Significant Impact on Freeze-Drying Behavior

Nathaniel Milton, Ph.D.

Product Development, Eli Lilly and Co.

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Types of Freeze-Drying Behavior: Crystallization of Nafcillin During Annealing

Nathaniel Milton, Ph.D.

Product Development, Eli Lilly and Co.

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B. Primary Drying The sublimation of ice from the frozen solution to create a dried layer of solute Solute must form a rigid structure to support its weight after the removal of ice. Maintaining product below the collapse temperature is critical to produce acceptable material Consequences of improper temperature control
Collapse product Shrunken freeze dried plug Melt-back

Nathaniel Milton, Ph.D.

Product Development, Eli Lilly and Co.

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Product Collapse - during freeze drying product temperature exceeds the collapse temperature and the material collapse as ice is sublimed. Fill volume Solute Ice

After ice sublimed a dried residue of solute is produced.

Nathaniel Milton, Ph.D.

Product Development, Eli Lilly and Co.

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Types of Freeze-Drying Behavior: Collapse

Nathaniel Milton, Ph.D.

Product Development, Eli Lilly and Co.

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Example Of Collapse Annealed vs. Unannealed Sucrose/Glycine Formulations

Nathaniel Milton, Ph.D.

Product Development, Eli Lilly and Co.

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Significance of Temperature

Collapse temperatures are formulation dependent During Freeze Drying


Primary drying (I.e., ice sublimation), Glass transition temperature, Tg


T<<Tg Tg Semi-solid T>>Tg "Fluid" Liquid

"Rigid" Solid

Increasing molecular mobility & "reactivity"

Nathaniel Milton, Ph.D.

Product Development, Eli Lilly and Co.

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How is Product Temperature Controlled during Primary Drying? Product temperature is controlled indirectly: a. Chamber pressure - Heat Transfer - Mass Transfer (Product Resistance) b. Shelf temperature - Heat Transfer

Condensing coils

T
Freeze Dryer Shelf
Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 22

Properly dried material produces a well formed cake with no apparent shrinkage.

Important Points about Primary Drying Product temperature is critical during primary drying Changes in product temperature during drying may influence appearance of final product Damage which occurs during primary drying can not be repaired.
Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 23

Freeze drying is a process where heat and mass transfer are coupled!

Pc

m
Rp Po Kv Ice Q Shelf Temp - Ts Ti Tb

Nathaniel Milton, Ph.D.

Product Development, Eli Lilly and Co.

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Influence of Vapor Flow Resistance on Product Temperature


Water vapor must have enough energy to pass through the dried layer and to the condenser As resistance increases more energy (heat) is needed for water vapor to escape Product temperature increases with increasing resistance

Nitrogen Vacuum Interface

m
Rp
Ice
Heat
Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. Dried Layer Ice/Produce Interface Water vapor

Mass

Ice

Heat

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Why Does Product Collapse => Product Resistance


Solution Frozen Product Heated Ice Sublimes (Heat Removed) Product Resistance Increases Vapor Pressure Increases

No

Dry
?

No

Is T > Tc
?

Temperature Increases

Yes

Yes

Dry Cake
Nathaniel Milton, Ph.D.

Collapse
26

Product Development, Eli Lilly and Co.

Heat and Mass Transfer Equations Describing Freeze Drying

m =

A p ( Po Pc ) R p + Rs

A p ( Po Pc )

where
Eq. 1

Rp

Pc = chamber pressure/ (above dried solute) Rp = product resistance Rs =stopper resistance . m = rate of sublimation Po = vapor pressure of ice

Relationship between chamber pressure and vapor pressure of ice (I.e., ice temperature)

Av Kv (TS T TI ) m= = s s

Eq. 2

Av = surface of vial Kv = vial heat transfer coefficient Ts = shelf temperature Hs = enthalpy of sublimation T = temperature difference across ice slab TI = temperature at the ice interface

Relationship between shelf temperature and ice temperature


Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 27

The relationship between the vapor pressure of ice and ice temperature is

6144.96 27315 . TI = ln Po 24.01849


Combining Eq. 1, 2, and 3 yields Eq. 4
Rp =

Eq. 3

Ap Av

( Po Pc )

6144.96 Kv Ts T 27315 . ln( Po 24.01849)

Eq. 4

Eq. 4 describes the relationship between product resistance, vapor pressure of ice (product temperature), the shelf temperature, and chamber pressure).

Nathaniel Milton, Ph.D.

Product Development, Eli Lilly and Co.

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1000

B A
Vapor Pressure of Ice (torr 10-3)
800

600

400

C
200

10

12

14

16

18

Product Resistance (torr

cm2 hr

gm-1)

Regression analysis of vapor pressure of ice and product resistance data collected at a shelf temperature of 20C and 100 millitorr (A), shelf temperature 0C and 100 millitorr (B), and shelf temperature of -20C and chamber pressure 80 millitorr with Eq. 4 assuming a 2 degree temperature gradient across the ice slab.

Increase Rp related to increase Po (i.e., Temperature)


Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 29

C. Secondary Drying
Removal of adsorbed water from the dried solute (no ice present)

5% water

0.1% water

Controls moisture level in product to maintain proper chemical and physical stability. Reversible process (can de-humidify and humidify product to change moisture content)
Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 30

Critical Points for Consideration


Degradation Concentration effects during freezing Reconstitution Disperse material in freeze dried cake Collapse Glycine and mannitol bulking agents raise Tc Damage during freezing and drying Cryoprotectants and lyoprotectants Stabilizers (amorphous) Sugars (sucrose, lactose), glycine Adherence to glass Surfactants, silicone
Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 31

Critical Points for Consideration


Physical state in frozen solution
Excipient and active pharmaceutical ingredient

Physical state in freeze dried powder


Impact on physical and chemical stability

Influence of processing conditions


Changes in thermal history can changed the physical state of material(s) and effect process compatibility and chemical stability

Understanding facilitates formulation development, process design and control


Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 32

Case Study
Nafcillin Sodium
N. Milton and S. L. Nail. The physical state of nafcillin sodium in frozen aqueous solutions and freeze-dried powders. Pharmaceutical Development and Tech, 1 (3), 269-277, 1996.

Buffers and pH control

Nathaniel Milton, Ph.D.

Product Development, Eli Lilly and Co.

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Isothermal Crystallization

Photomicrographs of 25% nafcillin sodium frozen solution using crossed polars and first order red compensator: A) frozen solution at -10C, B) frozen solution at -4C, C) frozen solution after 5 minutes at -4C, and D) frozen solution after 15 minutes at -4C.
Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 34

Solid state decomposition at 50C of nafcillin sodium unannealed (open symbols) and annealed (closed symbols) stored at 11% (squares) and 23% (triangles) relative humidity. Unannealed less stable than Annealed
Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 35

Case Study - Buffer Selection


Preliminary data suggested the optimal solution pH between 4 - 5 Formulations prepared with acetate, citrate and tartrate buffers All buffers were prepare in equal molar concentrations and adjusted with NaOH Acetate buffer least stable (Why?)
Nathaniel Milton, Ph.D. Product Development, Eli Lilly and Co. 36

Effect of various Buffers on Stability (100 mM)


pH 4.0 22 20 18 16 14 12 10 8 6 4 2 0 0
22 pH 4.5 20 18 16 % TRS 14 12 10 8 6 4 2 0

Acetic acid Citric acid Tartaric acid

Acetic acid Citric acid Tartaric acid

% TRS

Time, (Weeks)

Time, (Weeks)

Nathaniel Milton, Ph.D.

Product Development, Eli Lilly and Co.

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Review of Data
pH of reconstituted acetate buffer formulation increased 1.58 - 1.78 pH units Acetic acid component of buffer system Acetic acid is volatile and evaporates Loss of acetic acid leads to increase in formulation pH and poor stability Avoid use of volatile buffer species or other materials (I.e., ammonium salts)

Nathaniel Milton, Ph.D.

Product Development, Eli Lilly and Co.

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Conclusions
Advantages of Freeze Drying 1. Low particulate contamination 2. Solid more stable than solution 3. Low temperature process => less in-process degradation 4. Compatible with aseptic processing 5. Can be easily reconstituted Disadvantages of Freeze Drying 1. Cost => capital expenditures, process long and expensive 2. Difficult to produce crystalline material

Nathaniel Milton, Ph.D.

Product Development, Eli Lilly and Co.

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Conclusions
Freeze drying provides a method of drying temperature labile materials. The freeze drying process is divided into 3 steps: - Freezing - Primary Drying - Secondary Drying Changing the freezing, primary drying, or secondary drying conditions can influence the physical and chemical stability of the final product Freeze drying is often the last choice in methods for drying materials, because the cost and time required.

Nathaniel Milton, Ph.D.

Product Development, Eli Lilly and Co.

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