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Lyophilization TechnologyThe theory and practice of freeze-drying

of pharmaceuticals

M. Kamat and M. Yelvigi

The Center for Professional Advancement

January 30-31, 2013

New Jersey, USA

M. Kamat Jan, 2013

History

• Freeze-dried plasma/serum in WWII– Even today: At-least 10 donors, 2 years RT, 200 mL water for constitution

• Bacteria/vaccines• Food industry: coffee, fruits• Military Rations/Astronaut Food/Hikers' food

• Museum articles• Restoration of old artifacts (sunken ships, water-damaged libraries)

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Lyophilized Pharmaceuticals

• More than 140 lyophilized injectables– Ampoules, syringes, vials, and large bottles

• > 30 biologicals, vaccines

• Freeze-dried skin grafts and tissues

• Quick-dissolve oral tablets (Claritin Reditabs)

M. Kamat Jan, 2013

Definition• Lyophilization is a coupled heat-mass-transfer

process where the frozen solvent, usually water, is removed initially by sublimation under the conditions of reduced pressure and sub-zero temperatures, and then by desorption under the conditions of reduced pressure and above zero temperatures to yield a dry product.

• Whereas, freeze-drying may be defined as vacuum drying below 0 ºC (coffee, cereals, space food, animals etc.)

• Keywords:Required UndesirableFrozen InstabilitySublimation Collapse/meltbackDesorption Vial breakageDry Product High moisture

Reconstitution Problems

5We will use freeze drying and lyophilization as synonymous for this course

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Why Lyophilization of Pharmaceuticals

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Advantages:1. Stability: Aqueous Stability

• To make sure that no more than 10% degradation in 2-4 years

• Thermal Stability : High temperature conventional drying may not be suitable

2. Improved Product Characteristics: • Improved kinetic solubility (because of

porosity and very large surface area)• Usually freeze-dried product is amorphous• Variable recon. volume to get conc. (SubC

conc.?)3. Other Advantages:

• Shipping advantage (low weight)• Less interaction with primary package of

highly alkaline solutions• Less problems with glass delamination

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Why Lyophilization of Pharmaceuticals

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Advantages: cont.

4. Accuracy of dosage• Ease of filling complex formulation as a solution

• Doses as low as 0.1 mL (vaccines, GF etc.)5. Well controlled headspace

• Nitrogen, Argon (oxygen and some time Freon too)

• Vacuum6.Ease of Operation:

• Liquid filling operation: Automatic, accurate, well controlled (well established)

• In-line sterilization filtration in the final containerM. Kamat Jan, 2013

Stability of Solution and Lyophilized Forms

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* From Package Insert Information

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1. API/Excipients substance need to be Sterile• Handling: aseptic powder, bins, etc.

2. Fill Accuracy• <100mg powder filling (auger, piston) is

difficult

3. Particulate issues

4. Dusting problem

5. Environmental Factors:• Humidity, Oxygen, Electrostatic Charge

6. Powder Characteristics (difficult):• Flowability and segregation• Particle Size, PSD, blend uniformity,

Bulk density, cohesiveness)

If thermal stability is not an issue why not powder fill?

Most of the large dose antibiotics (penicillins, cephalosporins) are powder filled in billions of quantities

M. Kamat Jan, 2013

Disadvantage of lyophilization

• Additional unit process• One more thing that can go wrong and that too irreversibly !!)

• Costly and complex equipment needing greater maintenance

• Transfer and scale-up issues compared to solution products

• Long cycles (up to even 7 days): Cleaning, sterilization, leak-testing may add another 24 hours

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Physical Chemistry of Lyophilization:

Points to Consider :

• Behavior of water during freezing• Heat Transfer Phenomenon• Mass Transfer Phenomenon• Coupling of Heat and Mass Transfer• Requirements of Process

M. Kamat Jan, 2013

Physical Chemistry of Lyophilization:

• Points to Consider

• Behavior of solutions during freezing• Sublimation Process• Heat Transfer Phenomenon• Mass Transfer Phenomenon• Coupling of Heat and Mass Transfer• Requirements of Process

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Phase diagram of water

• Sublimation occurs between the solid and the vapor phase regions.

• Since only two phases are present (solid line), solid ice and the vapor ice are in equilibrium.

• The diagram also says that once Temp of ice is fixed, the vapor pressure over ice is automatically fixed, and vice-a-versa. 13

Triple point

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~ 100 mTorr

~ 100 mTorr

Ref. point 1 mBar = 1000 µbar = 750 mTorr or 750 microns 0.33 mBar = 200 microns1 atmosphere = 760 mm = 760,000 mTorrM. Kamat Jan, 2013

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Energetic of Phase Change

In Regular Evaporation Drying :

VaporizationLiquid Water Water Vapor (Hvap)

In Sublimation Drying (Lyophilization)

Sublimation (no liquid)Ice Water Vapor (Hsub)

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Energetic of Phase Change

Sublimation Drying (Lyophilization)

Sublimation (no liquid)Ice Vapor state (Hsub)

Sublimation involves solid, liquid, and gas transitions and need energy H2Oice (-40 C) H2Ovapor (25 C), Hsub

1. H2Oice (-40 C) H2Oice (0 C), H1

2. H2Oice (0 C) H2Oliq (0 C), H2

3. H2Oliq (0 C) H2Oliq (25 C), H3

4. H2Oliq (25 C) H2Ovapor (25 C), H4

Adding all these reactions, Hsub = H1 + H2 + H3 + H4

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Heat Energy Must Be Provided for Sublimation to Continue:

• Heat Energy must be provided for sublimation to continue

• How much heat to be supplied ?– 676 calories/gm of ice to be sublimed at ºC•Latent heat of fusion (78 Calories) + Latent heat of vaporization (598 Calories)

• If excess heat (more than required for phase change) is supplied, the heat will be used to raise the temperature of the product (not just for phase change) and .....Eventually melt the ice.

M. Kamat Jan, 2013

Boiling Water(Phase Change)

Temp=100 C

Temp= ~600 C

Temp= ~600 C

Probe in pot-full of water on hot plate

Probe in emptied pot on hot plate

Boiling Water in Kettle

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Heat Energy Must Be Provided for Sublimation to Continue:

• What is the heat source- From the heated shelves in the lyophilizer Chamber (some cases: ambient heat, IR, MW etc.)

• How to increase the rate of sublimation- Increase the driving force1. Increase the heat supply (shelf

temperature)2. Increase the product temperature

Limit: (maximum allowable temperature)3. For every 10 ºC rise in product temp,

the rate of drying doubles

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ImportantImportant

• The low pressure above the ice keeps the product frozen

• The heat is transferred into the Vial (Heat-Transfer)

• The water vapor is transferred out of vial(Mass-Transfer)

• The two transfer processes must be equal to keep the product frozen and sublimation process to continue

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The Water Vapor Is Transferred Out of Vial

• The vapor then flows out of chamber into the condenser section and gets deposited as ice on cold surfaces of condenser plates.

• In old times : • chemical traps (P2O5, silica desiccants)• (and in food industry) directly to the pump/ballast (and then oil change)

• The coldness of condenser does not affect the drying rate as long as it is colder than the product temperature

• Above certain temperature, though, the ice condensation power may decrease

• Very low condenser temperatures are not needed for sublimation to happen: Just collect the sublimate

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Heat Transfer Phenomena

Flow of Heat :

Heating Medium Shelf Interior Shelf Surface (thru the trays) Under the Vial Bottom Surface of Vial Bottom of Ice Through the Ice Sublimation Front

Rate of heat input = W)TT(d

184.4Q i,CS

Where, is the thermal conductivity of the container,d is the thickness of the base of the containerTs = Shelf temperatureTc,i = Temperature at the ice interface

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Mass Transfer Phenomenon

We will discussThis later

Vent

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Heat and Mass transfer processes

Energy (in) = Energy (out)(heat) (sublimation)

Heat transfer rate = Hs X mass transfer rate

Rate of heat input = Heat of sublimation X Rate of mass transfer

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Effect of Resistance to Mass Transfer

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Key Process Parameters

Tp (product temperature): Keep the product below TcriticalPc (chamber pressure): Keep sublimation process onTs (shelf surface temp): Provide energy for sublimation

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Factors Which May Affect the Cycle

Action Effect on Cycle

Increase Product temperature Short

Decrease dried product resistance Short(Freezing modifications)

Use of Trays Long

Better Contact of Glass Short

Increase Chamber Pressure Short(Up to certain limits)

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Process Parameters

Independent Parameters (all programmable

variables)Not affected by the

characteristics and the load of the

product

• Shelf Temperature (fluid)

• Time Duration (soaks)• Ramping

Dependent Parameters (non-programmable

variables)Affected by the

characteristics andthe load of the product

• Condenser Temperature• Chamber Pressure• Product Temperature• Product drying Time

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Stages of Lyophilization

• Fill the solution in the vials. Place stoppers• Freezing the product on FD Shelves• Start Cooling the condenser• Produce Vacuum in the dryer• Open the isolation Valve• Check Pressure and Heat the product• Start Primary drying• Continue with Secondary Drying• End-of-Drying • Stopper and Remove the Product• QC Testing

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Schematics of a Lyophilizer

32From: Sundaram et al; BioPharm International, Volume 23, Issue 9, Sep 2010M. Kamat Jan, 2013

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Lyophilizer Chamber

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Lyophilizer Units

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ChamberCondenser

Vacuum PumpsM. Kamat Jan, 2013

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FREEZE DRYING OF COFFEE INVOLVES FOUR STEPS:

•Pre-freezing coffee concentrate (40-45%) up to -5/-10 °C followed by foaming.

•Freezing of the pre-frozen coffee liquor at -50 °C in a blast freezer.

•Sizing of the fr0zen coffee particles to a granular size of 3X3mm.

•Sublimation of the ice in a vacuum freeze dryer (VFD) under vacuum (0.5 torr) and controlled temperature.

M. Kamat Jan, 2013