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PROCESSO DI LIOFILIZZAZIONE
06/01/2010 1
FREEZE-DRYING PROCESS
Principle and Practice
Carlo VECCHIO
Pharmaceutical Technologies
& Development
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INTRODUCTION
- removed by sublimation
in a vacuum environmental.
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INTRODUCTION
- microorganisms
- foods
- pharmaceutical products.
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INTRODUCTION
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INTRODUCTION
5. absence of powder
(particulate contamination is minimized).
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PROCESS OVERVIEW
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Schematic diagram of freeze drier
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PROCESS OVERVIEW
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PROCESS OVERVIEW
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PROCESS OVERVIEW
DIAGRAM OF VIAL DURING PRIMARY
DRYING After this pressure is reached,
heat is applied to the shelves
to provide the energy required
for sublimation of ice.
As drying proceeds, a
receding boundary can be
observed in the vial as the
frozen layer decreases in
thickness and the thickness of
partially dried solids increases.
- adsorbed to, or
- trapped by,
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PLOT OF PROCESS VARIABLES DURING FREEZE DRY CYCLE
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PROCESS OVERVIEW
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PROCESS OVERVIEW
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PROCESS OVERVIEW
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PROCESS OVERVIEW
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THE FREEZING PROCESS
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PHASE DIAGRAM OF WATER
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PHASE DIAGRAM OF WATER
The 4.58 mm Hg refers
to the water vapor
pressure, not the total
system pressure.
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FREEZING OF AQUEOUS SOLUTIONS
Temperature Vs. Time for Freezing of NaCl/water
At the point c,
crystallization of
concentrated interstitial
fluid is initiated: an
eutectic mixture of
crystalline NaCl/ice.
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Phase Diagram of NaCl/water
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EUTECTIC TEMPERATURES FOR AQUEOUS
SOLUTIONS OF VARIOUS COMPOUNDS
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EUTECTIC TEMPERATURE
If the product exceeds the Te, drying takes place from liquid
instead of the solid.
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TEMPERATURE VS. TIME FOR FREEZING OF AMORPHOUS SOLUTE
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GLASS TRANSITION
(OR COLLASPE) TEMPERATURE
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DRAWING OF MICROSTRUCTURE FOR CRYSTALLINE AND
AMORPHOUS SOLUTES UPON FREEZING
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PHASE DIAGRAM FOR AN AMORPHOUS SOLUTE
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PHASE DIAGRAM FOR AN AMORPHOUS SOLUTE
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GLASS TRANSITION TEMPERATURE OF
VARIOUS COMPOUNDS
Dextran - 9°C
Ficoll - 19.5°C
Fructose - 48°C
Glucose -40 to 43°C
Sucrose - 32 to 34°C
Maltose -32°C
Trehalose - 29.5°C
Sorbitol -45 to 51°C
Lactose - 32°C
Ovalbumin - 10°C
Gelatin - 8 to 10°C
Polyvinylpyrrolidone -23 to 24°C
Methylcellulose -9°C
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THE PROCESS
Freezing
Cooling the material until completely frozen
Primary drying
Sublimation of ice from product reducing
pressure in the chamber and providing heat to
the product
Secondary drying
Desorption of residual moisture from the product
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PROCESS
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CHARACTERISTICS
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CHARACTERISTICS
- micro-organisms (sterile),
is an essential attribute.
- eutectic temperature
- degree of super-cooling
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SOLVENTS
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ORGANIC SOLVENTS
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ORGANIC SOLVENTS
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ADDED SUBSTANCES
Bulking agents
For very low dose products, the minimum practical fill volume
results in a solute concentration so low that the dried product
layer formed does not have sufficient mechanical strength to
withstand the force of flowing water vapor during primary
drying: the dried product is “blown” all over the drier.
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ADDED SUBSTANCES
Bulking agents
Most commonly used bulking agents include:
- mannitol,
- lactose,
- dextran,
- sorbitol,
- sucrose,
- dulcitol,
- gelatin,
- bovine serum albumin,
- glycine,
- polyvinylpyrrolidone,
- sodium chloride,
- ficoll 70 (a branched polymer synthesized from sucrose and epichlorohydrin).
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ADDED SUBSTANCES
Cryoprotectant agents
If the damage during freezing is a problem, a cryo-protective
agent such as sugars (sucrose, trehalose) or bovine serum
albumin may be added.
Buffer agents
If degradation is a risk during freezing due pH change, buffers
(acetate, citrate, phosphate, glutamate) may be added to
maintain the pH in a region desirable for the stability of a drug.
Tonicity adjusters
Tonicity adjusters to avoid hemolysis or crenation of red blood
cells in isotonic solution, e.g., NaCl 0.9% and dextrose 5%, the
cell maintain their “tone”
(hypotonic solution < 280 mOsm/kg; Hypertonic solution >360 mOsm/kg).
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ADDED SUBSTANCES
Antioxidants
They prevent oxidation of the drug (sodium bisufite and
metabisulfite, tocopherols, butylhydroxyanisole, ascorbic
acid,)
Preservatives
They avoid risk of contamination in containers intended for
multiple injections (benzalkonium and benzethonium
chloride, benzyl alcohol, methyl and propyl parabens,
chlorobutanol)
Surfactants
They help solubilization (poloxyethylene sorbitan
monooleate, sorbitan monooleate).
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ADDED SUBSTANCES
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FREEZING OF AN AQUEOUS SOLUTION
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FREEZING OF AN AQUEOUS SOLUTION
A fast ice growth also help to prevent the denaturation of proteins (if
present) which may result from prolonged exposure to strong
concentrations of salts because of slow ice growth.
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FREEZING OF AN AQUEOUS SOLUTION
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FREEZING OF AN AQUEOUS SOLUTION
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FREEZING OF AN AQUEOUS SOLUTION
However, freezing products outside the chamber has certain
disadvantages:
- increased chance of contaminating the product because of the
need for extra handling
- possibility that the frozen product may partially melt during
transfer to the freeze-dryer
- moisture from the atmosphere may condense and form frost on
the containers of the frozen product or on the necessarily pre-
cooled shelves of the freeze-dryer while it is being loaded.
This frost:
-makes loading difficult,
-increases the quantity of ice to be sublimed in the early stages of
primary drying,
-may cause the containers to make poor thermal contact with the
shelves in the freeze-dryer
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STAGES OF FREEZING
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STAGES OF FREEZING
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FREEZING OF AN AQUEOUS SOLUTION
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FREEZING OF AN AQUEOUS SOLUTION
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THERMAL TREATMENT
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THERMAL TREATMENT
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TRANSITIONS OF PHASE
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TRANSITIONS OF PHASE
Differential Scanning Calorimetry
(DSC) can be usefully employed to
determine the phase transitions in the
frozen systems.
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TRANSITIONS OF PHASE
When the sample undergoes a transition, its temperature
differs from that of the reference and heat either flows to or
away from the sample.
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TRANSITIONS OF PHASE
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THERMAL TREATMENT
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THERMAL TREATMENT
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THERMAL TREATMENT
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THERMAL TREATMENT
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X-RAY DIFFRACTION SPECTRA OF FREEZE DRIED
CEFAZOLIN
The lower is of
material which was
thermally treated
before drying.
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INDUCTION TO THE CRYSTALLIZATION
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CRYSTALLIZATION OF ACTIVE COMPOUND
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CRITICAL TEMPERATURES
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METHODS FOR STUDYING FREEZING
CHATACTERISTICS
-Thermal Analysis
(DSC cooling and warming)
- Electrical Resistance
(mobility of the ions)
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METHODS FOR STUDYING FREEZING
CHATACTERISTICS
Thermal Analysis
It may be usefully employed:
- DSC cooling thermograms may be used to
determine the temperature of complete
solidification (Tcs)
- DSC warming thermograms may give a direct
measurement of Tg and the eutectic temperature
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METHODS FOR STUDYING FREEZING
CHATACTERISTICS
Electrical Resistance
This method involves the simultaneous monitoring of
resistance and temperature of a frozen sample.
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Electrical Resistance
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METHODS FOR STUDYING FREEZING
CHATACTERISTICS
Freezing/Freezing Drying microscope
The freezing microscope, unlike all the above
methods, allows direct observation of the sample
being frozen or warmed.
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SUPERCOOLING AND DEGREE OF
CRYSTALLIZATION
The size of the ice crystals determines the size of the pores
(or channels) created during ice sublimation and
determines the surface area of the porous solid produced
by the sublimation process.
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DEGREE OF SUPERCOOLING
According to Jennings:
- a high degree of supercooling leads
to homogeneous network of fine pores
- a low degree of supercooling yields
a heterogeneous plug structure with a
thick skin on the surface and a very
fine pores on the bottom.
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DEGREE OF SUPERCOOLING
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RESISTANCE TO THE FLOW
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Typical pressures in primary drying and
various resistances
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RESISTANCE OF THE DRIED PRODUCT
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SUBLIMATION RATE
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SUBLIMATION RATE
The key to successful drying is to remove the water vapor from the
frozen cake without allowing liquid water to form.
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EUTECTIC MELTING AND COLLAPSE
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EUTECTIC MELTING AND COLLAPSE
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HEAT TRANSFER
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HEAT-TRANSFER COEFFICIENT
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EFFECT OF CHAMBER PRESSURE ON PRIMARY DRYING
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EFFECT OF CHAMBER PRESSURE ON
PRIMARY DRYING
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EFFECT OF CHAMBER PRESSURE ON
PRIMARY DRYING
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END POINT OF THE PRIMARY DRYING
Primary drying ends when all ice in all product containers has
been removed.
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SECONDARY DRYING
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END POINT DETERMINATION OF SECONDARY DRYING
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OPTIMIZATION OF THE LYOPHILIZATION PROCESS
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CYCLE TIME AND WORKING DAYS
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USE OF MICROPROCESSOR
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CONCLUSIONS
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CONCLUSIONS
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FREEZE DRY EQUIPMENT
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FREEZE DRY EQUIPMENT
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VACUUM SYSTEM
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SPEED OF A VACUUM PUMP
dP/dt = S / C (P-Ps)
where:
dP/dt= rate of change of pressure with time
S=pumping speed (volume/time)
C=volume of system to be evacuated
Ps=lowest attainable pressure.
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VACUUM PUMP
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REFRIGERATION
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REFRIGERATION
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HEAT TRANSFER FLUID
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STERILIZATION OF FREEZE DRYERS
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VACUUM INTEGRITY TEST
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SUMMARY
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