Lyophilization Technology

The 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

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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) M. Kamat Jan, 2013 2

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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 4

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

Frozen Sublimation Desorption

Undesirable

Instability Collapse/meltback Vial breakage Dry Product High moisture Reconstitution Problems

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

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Why Lyophilization of Pharmaceuticals

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 M. Kamat Jan, 2013 6

Why Lyophilization of Pharmaceuticals

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) Vacuum 6.

• • Ease of Operation: Liquid filling operation: Automatic, accurate, well controlled (well established) In-line sterilization filtration in the final container M. Kamat Jan, 2013 7

Stability of Solution and Lyophilized Forms

Product Caspofungin/Cancidas Cyclophosphamide/Cytoxan Carboplatin/Paraplatin Fosaprepitant/Emend Gemcitabine/Gemzar Ixabepilone/Ixempra Infliximab/Remicade Asoarginase/Erwinase

* From Package Insert Information

Solution Form* 1 hr at RT 1 week (13% loss) Particulates 24 hr at RT 24 hr at RT 1 hr at RT 3 hr at RT 4 hr at RT M. Kamat Jan, 2013 Lyophilized Product 2 years 3 years 2 years > 2 years > 2 years > 2 years > 2 years > 2 years 8

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

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)

quantities

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 M. Kamat Jan, 2013 10

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

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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 M. Kamat Jan, 2013 12

Phase diagram of water

Triple point

• • • 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 13

~ 100 mTorr

Ref. point

~ 100 mTorr

1 mBar = 1000 µbar = 750 mTorr or 750 microns 0.33 mBar = 200 microns 1 atmosphere = 760 mm = 760,000 mTorr

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Energetic of Phase Change

In Regular Evaporation Drying :

Vaporization

Liquid Water Water Vapor (  Hvap) In Sublimation Drying (Lyophilization) Ice Sublimation (no liquid) Water Vapor (  Hsub) M. Kamat Jan, 2013 16

Energetic of Phase Change

Sublimation Drying (Lyophilization) Ice Sublimation (no liquid) Vapor state (  Hsub)

Sublimation involves solid, liquid, and gas transitions and need energy H 2 O

2. H

ice

2 O

(-40

ice  C

)

1. H 2 O ice (-40  C) (0  C) 3. H 2 O liq (0  C) 4. H 2 O liq (25  C)

H 2 Ovapor (25

 C

),



Hsub

H 2 O ice (0  C), 

H1

H 2 O liq (0  C), 

H2

H 2 O liq (25  C), 

H3

H 2 Ovapor (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.

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Boiling Water (Phase Change)

Boiling Water in Kettle

Temp=100 C Temp= ~600 C Temp= ~600 C Probe in pot-full of water on hot plate

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Probe in emptied pot on hot plate

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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 force 1. Increase the heat supply (shelf temperature) 2. Increase the product temperature 3.

Limit: ( maximum allowable temperature ) For every 10 ºC rise in product temp, the rate of drying doubles M. Kamat Jan, 2013 20

Important

• 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 M. Kamat Jan, 2013 21

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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Flow of Heat : Heat Transfer Phenomena 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 =

Q  4 .

184  d ( T S  T C , i ) W  Where, is the thermal conductivity of the container, d is the thickness of the base of the container Ts = Shelf temperature Tc,i = Temperature at the ice interface M. Kamat Jan, 2013 23

Mass Transfer Phenomenon

We will discuss This later

Vent

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Heat and Mass transfer processes

Energy (in) (heat) Heat transfer rate = = Energy (out) (sublimation) Hs X mass transfer rate

Q = H x ( P - P ) R total

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):

Pc

(chamber pressure):

Ts

(shelf surface temp): Keep the product below Tcritical Keep sublimation process on Provide energy for sublimation M. Kamat Jan, 2013 28

Factors Which May Affect the Cycle

Action Increase Product temperature Decrease dried product resistance (Freezing modifications) Use of Trays Better Contact of Glass Increase Chamber Pressure (Up to certain limits) M. Kamat Jan, 2013 Effect on Cycle Short Short Long Short Short 29

Process Parameters

Independent Parameters (all programmable variables)

Not affected by the characteristics and the load of the product

Dependent Parameters (non-programmable variables)

Affected by the characteristics and the load of the product • • •

Shelf Temperature (fluid) Time Duration (soaks) Ramping

• • • •

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 M. Kamat Jan, 2013 31

Schematics of a Lyophilizer

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Lyophilizer Chamber

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Lyophilizer Units

Condenser Chamber Vacuum Pumps

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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.

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