LYOPHILIZATION (FREEZE-DRYING)-A REVIEW

ISSN 0976-111X

1IJPWR VOL 4 ISSUE 1 (Jan-Mar) – 2013

INTERNATIONAL JOURNAL OF PHARMA WORLD RESEARCH

(An International Quarterly Published Online Research Journal)

www.ijpwr.com E-mail:[email protected]

Title:

LYOPHILIZATION (FREEZE-DRYING)-A REVIEW

B.Venkateswara Reddy, B.Rasmitha reddy, P.Ujwala, K.Navaneetha

St.pauls college of pharmacy, Turkayamjal, R.R (dist),501510

ABSTRACT:

Freeze-drying is a relatively expensive process requiring long processing time.

Consequently, commercial freeze-drying processes are often neither robust nor efficient.

The design of an “optimized” freeze-drying process is not particularly difficult for most

products, as long as some simple rules based on well-accepted scientific principles are

followed. It is the purpose of this review to discuss the scientific foundations of the

freeze-drying process design and then to consolidate these principles into a set of

guidelines for rational process design and optimization. , guidelines are given for

selection of the optimal shelf temperature and chamber pressure settings required to

achieve the target product temperature without thermal and/or mass transfer overload of

the freeze dryer.

KEY WORDS:

Freez drying process, lyophilization equipment, freez dryers, process validation

http://www.ijpwr.com/

ISSN 0976-111X


INTRODUCTION:

DEFINITION:

Freeze-drying is a process of drying in which water is sublimed from the product

after it is frozen. It is a drying process applicable to manufacture of certain

pharmaceuticals and biologicals that are thermolabile or otherwise unstable in aqueous

solutions for prolonged storage periods, but that are stable in the dry state. The term

“lyophilization” describes a process to produce a product that “loves the dry state”.

ORIGIN:

Freeze-drying was actively developed during WWII. Serum being sent to Europe from

the US for medical treatment of the wounded required refrigeration, but because of the

lack of simultaneous refrigeration and transport, many serum supplies were spoiling

before reaching their intended recipients. The freeze-drying process was developed as a

commercial technique that enabled serum to be rendered chemically stable and viable

without having to be refrigerated. Shortly thereafter, the freeze-dry process was applied

to penicillin and bone, and lyophilization became recognized as an important technique

for preservation of biologicals. Since that time, freeze-drying has been used as a

preservation or processing technique for a wide variety of products. These applications

include the following but are not limited to: the processing of food, pharmaceuticals, and

diagnostic kits; the restoration of water damaged documents; the preparation of river-

bottom sludge for hydrocarbon analysis; the manufacturing of ceramics used in the

semiconductor industry; the production of synthetic skin; the restoration of

historic/reclaimed boat hulls.

THEORY:

The drugs which lose their viability in the liquid state and readily deteriorate if

dried in air at normal atmospheric pressures, these may be heat sensitive or they may

react readily with oxygen, so that in order to be stabilized, they must be dehydrated to a

http://en.wikipedia.org/wiki/Serum_%28blood%29

ISSN 0976-111X


solid state and this is carried out by freeze-drying also known as lyophilization,

gelsication or drying by sublimation . The dried product can be readily redissolved or

resuspended by the addition of water prior to use, a procedure known as reconstitution.

PRINCIPLE:

The main principle involved in freeze drying is a phenomenon called

sublimation, where water passes directly from solid state (ice) to the vapor state without

passing through the liquid state. Sublimation of water can take place at pressures and

temperature below triple point i.e. 4.579 mm of Hg and 0.0099 degree Celsius. The

material to be dried is first frozen and then subjected under a high vacuum to heat (by

conduction or radiation or by both) so that frozen liquid sublimes leaving only solid

,dried components of the original liquid. The concentration gradient of water vapor

between the drying front and condenser is the driving force for removal of water during

lyophilization.

Fig 1: Rate of drying of water

To extract water from foods, the process of lyophilization consists of:

1. Freezing the food so that the water in the food become ice;

2. Under a vacuum, sublimating the ice directly into water vapour;

3. Drawing off the water vapour;

ISSN 0976-111X


4. Once the ice is sublimated, the foods are freeze-dried and can be removed from

the machine.

TRADITIONAL LYOPHILIZATION TECHNOLOGY:

Traditional lyophilization is a complex process that requires a careful balancing of

product, equipment, and processing techniques.

For nearly 30 years, lyophilization has been used to stabilize many types of chemical

components. In their liquid form, many such biochemicals and chemical reagents are

unstable, biologically and chemically active, temperature sensitive, and chemically

reactive with one another.

Because of these characteristics, the chemicals may have a very short shelf life, may need

to be refrigerated, or may degrade unless stabilized. When performed properly, the

process of lyophilization solves these problems by putting reagents into a state of

suspended activity.

Lyophilization gives unstable chemical solutions a long shelf life when they are stored at

room temperature. The process gives a product excellent solubility characteristics,

allowing for rapid reconstitution. Heat- and moisture-sensitive compounds retain their

viability.

Most proteins do not denature during the process, and bacterial growth and enzyme

action, which normally occur in aqueous preparations, can be eliminated. Thus,

lyophilization ensures maximum retention of biological and chemical purity.

ISSN 0976-111X


PROCESSING:

There are four stages in the complete drying process: pretreatment, freezing, primary

drying, and secondary drying.

Freeze-dryingprocess:

Freeze drying is mainly used to remove the water from sensitive products, mostly of

biological origin, without damaging them, so they can be preserved easily, in a

permanently storable state and be reconstituted simply by adding water.

Examples of freeze dried products are: antibiotics, bacteria, sera, vaccines, diagnostic

medications, protein-containing and biotechnological products, cells and tissues, and

chemicals.

The product to be dried is frozen under atmospheric pressure. Then, in an initial drying

phase referred to as primary drying, the water (in form of ice) is removed by sublimation;

in the second phase, called secondary drying, it is removed by desorption. Freeze drying

is carried out under vacuum.

The conditions under which the process takes place will determine the quality of the

freeze dried product. Some important aspects to be considered during the freeze drying

process are as follows:

Pretreatment:

Pretreatment includes any method of treating the product prior to freezing. This may

include concentrating the product, formulation revision (i.e., addition of components to

increase stability and/or improve processing), decreasing a high vapor pressure solvent or

increasing the surface area. In many instances the decision to pretreat a product is based

ISSN 0976-111X


on theoretical knowledge of freeze-drying and its requirements, or is demanded by cycle

time or product quality considerations. Methods of pretreatment include: Freeze

concentration, Solution phase concentration, Formulation to Preserve Product

Appearance, Formulation to Stabilize Reactive Products, Formulation to Increase the

Surface Area, and Decreasing High Vapor Pressure Solvents.

Freezing:

Freezing means to transform the basic product by abstracting heat to create a state that is

suitable for sublimation drying. When an aqueous product is cooled down, at first crystal

nuclei are formed. The surrounding water will be taken up around these nucleation sites,

resulting in crystals of different sizes and shapes. Freezing speed, composition of the

basic product, water content, viscosity of the liquid, and the presence of non-crystallizing

substance are all decisive factors in determining the crystal shape and size and in

influencing the following sublimation process. Large crystals leave a relatively open

lattice after sublimation, while small ice crystals leave narrow spaces in the dried product

slowing down the removal of water vapour. The freezing point of pure water is 0°C. Any

other substances dissolved in the water will lower the freezing point; where inorganic

salts are present it may be considerably lower. If a weak solution is frozen, at first pure

ice will be separated, thereby increasing the concentration of dissolved substance in the

residual solution making its freezing point lower still. The effect of such freezing

concentration on the product is different from case to case and has to be taken into

account when selecting the most appropriate freezing technique.

The most suitable freezing technique for a specific product should be determined and its

parameters ascertained prior to sublimation drying. The freezing behavior of the product

may be investigated, for instance, using the resistance-measurement method.

Two different freezing methods are chiefly used for pharmaceutical products:

ISSN 0976-111X


1. Freezing by contact with cooled surface.

2. Rotation or dynamic freezing in a coolant bath.

The first method is a static freezing technique where a versatile freeze dryer must be

capable of adjusting the freezing rate to the specific product and should allow control of

the freezing speed. A final temperature of -50°C will in many cases be sufficient to meet

all requirements.

The second method is used wherever larger quantities of a liquid product are to be frozen

and dried in flasks or large bottles.

The appropriate freezing technique will also be chosen to produce a layer thickness of the

frozen product that is favourable for sublimation drying, i.e. not only uniform but also as

thin as possible to achieve a short drying time.

Primary Drying :

Fig 2: Phase Diagram for Water

At the beginning of the primary drying phase, sublimation of the ice takes place at the

surface. As the process continues, the subliming surface withdraws into the product, and

the evolving vapour must be conducted through the previously dried outer layers. This

means that the drying process depends on the speed of vapour transfer and removal as

ISSN 0976-111X


well as on the necessary heat of sublimation. The heat required for sublimation is

supplied to the product by convection and thermal conduction and in a small part by

thermal radiation. Apart from heat transfer by thermal conduction and radiation, it is most

important that the heat transfer by convection is optimized. It must be taken into account,

however, that due to the reduction of pressure in the drying chamber, convection will

practically cease at a pressure below 10-2 mbar. This is why, as a function of the required

sublimation temperature, the pressure in the drying chamber is adjusted during primary

drying to the highest permissible value. The sublimation heat is not needed at the product

surface, but at the boundary of the ice core that is withdrawing into the centre of the

product as drying proceeds. Whilst the flow of water vapour is from within the product to

the outside, the transfer of heat must be accomplished in the opposite direction from the

outside to the inside. Due to the low thermal conductivity of the dried product layers, the

temperature gradient required for heat transfer steadily increases. To avoid damage to the

product, the maximum admissible temperature for the dried product must not be

exceeded. On the other hand, care must be taken to maintain the required sublimation

temperature throughout drying, keep the heat supply to the ice-core boundary in

equilibrium with the heat requirement at that particular location, and avoid any

overheating of the sublimation zone. The primary drying phase continues until all the ice

contained in the product has been sublimated.

Secondary Drying

In the secondary or final drying phase the aim is to reduce the residual moisture content

in the product as much as necessary to ensure the product is in a permanently storable

state. The water bound by adsorption at the internal surface of the product has to be

removed. To achieve this, it is often necessary to overcome the capillary forces of the

water, and freeze drying plant must therefore be designed to give a high pressure gradient

during the secondary drying phase, as in most cases it is not possible to raise the product

ISSN 0976-111X


temperature without damaging the product. The secondary drying process must be

precisely controlled so that any over drying of the product will be safely avoided.

Fig 3: Typical freez drying cycle

After-Treatment:

This section refers to the manner in which the dried products, often very

hygroscopic owing to their large internal surface, can be protected after drying. If the

product is dried in bottles, flasks or vials, it appears logical to close these containers

immediately after drying before removal from the plant. For this purpose, special ribbed

rubber stoppers are placed in the necks of the bottles or vials before charging the plant

and, on termination of drying, are firmly pressed into the necks by a stoppering device.

The containers may be sealed under vacuum or under protective gas atmosphere. The

choice of method depends on the type of product. It is advisable in any case to vent the

drying chamber after termination of the drying cycle with dry nitrogen or inert gas up to

atmospheric pressure and not to use air, with high humidity, for venting.

Properties of freeze-dried products:

If a freeze-dried substance is sealed to prevent the reabsorption of moisture, the substance

may be stored at room temperature without refrigeration, and be protected against

http://en.wikipedia.org/wiki/Room_temperature

ISSN 0976-111X


spoilage for many years. Preservation is possible because the greatly reduced water

content inhibits the action of microorganisms and enzymes that would normally spoil or

degrade the substance.

Freeze-drying also causes less damage to the substance than other dehydration methods

using higher temperatures. Freeze-drying does not usually cause shrinkage or toughening

of the material being dried. In addition, flavours, smells and nutritional content generally

remain unchanged, making the process popular for preserving food. However, water is

not the only chemical capable of sublimation, and the loss of other volatile compounds

such as acetic acid (vinegar) and alcohols can yield undesirable results.

Freeze-dried products can be rehydrated (reconstituted) much more quickly and easily

because the process leaves microscopic pores. The pores are created by the ice crystals

that sublimate, leaving gaps or pores in their place. This is especially important when it

comes to pharmaceutical uses. Freeze-drying can also be used to increase the shelf life of

some pharmaceuticals for many years.

Common Lyophilized Products:

Common Lyophilized Products Pharmaceuticals – large and small molecules Bacteria

Viruses Vaccines Plasma Small Zoological Specimens (Taxidermy) Fruit Coffee Flowers

Water-Damaged Documents.

LYOPHILIZATION EQUIPMENT:

There are essentially three categories of freeze-dryers: the manifold freeze-dryer, the

rotary freeze-dryer and the tray style freeze-dryer. Two components are common to all

types of freeze-dryers: a vacuum pump to reduce the ambient gas pressure in a vessel

containing the substance to be dried and a condenser to remove the moisture by

condensation on a surface cooled to −40 to −80 °C (−40 to −112 °F). The manifold,

http://en.wikipedia.org/wiki/Microorganism

http://en.wikipedia.org/wiki/Enzyme

http://en.wikipedia.org/wiki/Decomposition

http://en.wikipedia.org/wiki/Dehydration

http://en.wikipedia.org/wiki/Sublimation_%28chemistry%29

http://en.wikipedia.org/wiki/Pharmaceutical

ISSN 0976-111X


rotary and tray type freeze-dryers differ in the method by which the dried substance is

interfaced with a condenser. In manifold freeze-dryers a short usually circular tube is

used to connect multiple containers with the dried product to a condenser. The rotary and

tray freeze-dryers have a single large reservoir for the dried substance.

Rotary freeze-dryers are usually used for drying pellets, cubes and other pourable

substances. The rotary dryers have a cylindrical reservoir that is rotated during drying to

achieve a more uniform drying throughout the substance. Tray style freeze-dryers usually

have rectangular reservoir with shelves on which products, such as pharmaceutical

solutions and tissue extracts, can be placed in trays, vials and other containers.

Manifold freeze-dryers are usually used in a laboratory setting when drying liquid

substances in small containers and when the product will be used in a short period of

time. A manifold dryer will dry the product to less than 5% moisture content. Without

heat, only primary drying (removal of the unbound water) can be achieved. A heater must

be added for secondary drying, which will remove the bound water and will produce a

lower moisture content.

Tray style freeze-dryers are typically larger than the manifold dryers and are more

sophisticated. Tray style freeze-dryers are used to dry a variety of materials. A tray

freeze-dryer is used to produce the driest product for long-term storage. A tray freeze-

dryer allows the product to be frozen in place and performs both primary (unbound water

removal) and secondary (bound water removal) freeze-drying, thus producing the driest

possible end-product. Tray freeze-dryers can dry products in bulk or in vials or other

containers. When drying in vials, the freeze-dryer is supplied with a stoppering

mechanism that allows a stopper to be pressed into place, sealing the vial before it is

exposed to the atmosphere. This is used for long-term storage, such as vaccines.

http://en.wikipedia.org/wiki/Biological_tissue

ISSN 0976-111X


Improved freeze drying techniques are being developed to extend the range of products

that can be freeze dried, to improve the quality of the product, and to produce the product

faster with less labor.

A lyophilizer consists of a vacuum chamber that contains product shelves capable of

cooling and heating containers and their contents. A vacuum pump, a refrigeration unit,

and associated controls are connected to the vacuum chamber.

Chemicals are generally placed in containers such as glass vials that are placed on the

shelves within the vacuum chamber.

Cooling elements within the shelves freeze the product. Once the product is frozen, the

vacuum pump evacuates the chamber and the product is heated. Heat is transferred by

thermal conduction from the shelf, through the vial, and ultimately into the product.

Fig 4:freez drying process Fig 5:Sublimation drying

Lyophilization Container Requirements:

The container in which a substance is lyophilized must permit thermal conductivity, be

capable of being tightly sealed at the end of the lyophilization cycle, and minimize the

amount of moisture to permeate its walls and seal.

ISSN 0976-111X


The enclosed reagents can only remain properly lyophilized if the container in which they

are processed meets these requirements.

Lyophilization Heat Transfer:

Successful lyophilization is heavily dependent on good thermal conductivity. For this

reason, containers used in the lyophilization process must be capable of meeting a

number of heat-transfer requirements.

Such containers should be made of a material that offers good thermal conductivity;

should provide good thermal contact with the lyophilizer shelf, which is the source of

heat during processing; and should have a minimum of insulation separating the source of

heat from the product requiring heating.

Poor thermal conductivity often results from the use of containers made of materials with

low coefficients of heat transfer. It can also be caused by the shape, size, or quality of the

container.

It may come from thermal barriers, such as excessive amounts of material, which can act

as insulation, preventing energy from being transferred to the point at which the frozen

ice and dried product interface.

Poor thermal conductivity often results in a product that is not successfully lyophilized.

In a serum vial, the surface of the frozen cake must sublime first to allow the ice vapor to

escape.

Thereafter, the sublimation front moves as the drying proceeds. Generally, the

sublimation front simultaneously moves downward toward the bottom of the serum vial

and inward toward the center of the frozen cake (the core).

ISSN 0976-111X


If sublimation is not controlled—and it cannot be controlled when significant thermal

barriers exist—then portions of the chemicals may actually be vacuum-dried rather than

freeze-dried.

The processed product will then not possess the defined and reproducible characteristics

of a properly lyophilized material, such as maximized retention of activity, optimized

shelf life, rapid reconstitution, and a consistent finished cake.

FREEZE-DYERES:

Fig 6: Product viewable single shelf Fig 7: Freeze-dryer Development Freeze-dryer

Production Freeze-dryers:

Advantages:

1.Product is stored in dry state-few stability problems.

2.Product is dried without elevated temperatures.

3.Good for oxygen and/or air-sensitive drugs.

4.Rapid reconstitution time.

5.Constituents of the dried material remain homogenously dispersed.

6.Product is process in liquid form.

7.Sterility of product can be achieved and maintained.

ISSN 0976-111X


Disadvantages:

1. Volatile compounds may be removed by high vacuum.

2. Single most expensive unit operation.

3. Stability problems associated with individual drugs.

4. Some issues associated with sterilization and sterility assurance of the dryer chamber

and aseptic loading of vials into the chamber.

5. High energy costs (2-3times more than other methods).

6. Long process time.

PROCESS VALIDATION:

Control Operations: The phase change is monitored electronically by determining the

difference in resistance between the fluid and the solid as a function of temperature by

thermal analysis (measuring the difference in temperature between the sample and a

reference), by differential scanning calorimetry (the difference in heat input between the

sample and a reference , given that the change in temperature is a linear function).

Alternatively, one could also use a microscope to observe the formation of ice crystals In

this case, the eutectic point of the product must be precisely known in order to facilitate

the establishment of the cycle parameters for primary drying. Additionally, differing

product strengths, vial sizes, and batch sizes will often each have their own cycle

parameters Sterilization Process validation

Main Challenges of Lyophilization:

Development of formulation that meets all the necessary critical product attribute

requirements (quality appearance, potency, stability, recon time, etc) Accurate

determination of the “critical temperature” of final formulation necessary to determine

conditions of lyophilization cycle ( Tg ’, Te, Tc ) Establishment of temperature, pressure,

ISSN 0976-111X


and time cycle settings that can achieve best product quality in shortest possible time

Transfer and scale-up of lab-developed process to production scale process Keep all the

equipment running smoothly Special challenges in product development of lyophilized

biologic formulations and cycles

APLICATIONS:

Pharmaceutical and biotechnology : Pharmaceutical companies often use freeze-drying to

increase the shelf life of products, such as vaccines and other injectables.By removing the

water from the material and sealing the material in a vial, the material can be easily

stored, shipped, and later reconstituted to its original form for injection.

Food Industry :Freeze-drying is used to preserve food and make it very lightweight. The

process has been popularized in the forms of freeze-dried ice cream , an example of

astronaut food .

Technological Industry : In chemical synthesis , products are often freeze-dried to make

them more stable, or easier to dissolve in water for subsequent use. In bioseparations,

freeze-drying can be used also as a late-stage purification procedure, because it can

effectively remove solvents. Furthermore, it is capable of concentrating substances with

low molecular weights that are too small to be removed by a filtration membrane.

Other Uses : Organizations such as the Document Conservation Laboratory at the United

States National Archives and Records Administration (NARA) have done studies on

freeze-drying as a recovery method of water-damaged books and documents. In

bacteriology freeze-drying is used to conserve special strains .

ISSN 0976-111X


ADVANTAGES:

Lyophilization has many advantages compared to other drying and preserving techniques.

1. Lyophilization maintains food/ biochemical and chemical reagent quality because

they remains at a temperature that is below the freezing-point during the process

of sublimation; The use of lyophilization is particularly important when

processing lactic bacteria, because these products are easily affected by heat.

2. Food/biochemicals and chemical reagents which are lyophilized can usually be

stored without refrigeration, which results in a significant reduction of storage and

transportation costs.

3. Lyophilization greatly reduces weight, and this makes the products easier to

transport. For example, many foods contain as much as 90% water. These foods

are 10 times lighter after lyophilization.

4. Because they are porous, most freeze-dried products can be easily rehydrated.

Lyophilization does not significantly reduce volume, therefore water quickly

regains its place in the molecular structure of the food/ biochemicals and chemical

reagents.

Advantages of freeze drying over convectional drying:

Product Qualities Freeze Drying Conventional Drying Form of wet material to be dried

Whole, pieces, liquids, powders, slurries pieces Dry shape and form Maintained shriveled

Appearance Nearly same Shriveled Color Maintained faded Rehydration Fast slow Heat

exposure 0-150 °F 200-300 °F Oxygen exposure Very low high Retained volatiles

Excellent poor Advantages of freeze drying over convectional drying

ISSN 0976-111X


CONCLUSION:

The pharmaceutical industry has been revolutionized by the freeze- drying process. Life

saving medicines that have very short shelf lives are now being freeze-dried, shipped and

stored in many places that could never previously receive or store these medicines, thus

saving many lives. Another life saving substance in which freeze-drying has made

progress is in that of blood. Although freeze-drying blood is still extremely difficult due

to the very delicate nature of the blood cell, parts of the blood, as well as blood mixed

with glycerol, have been successfully freeze-dried, thus also saving lives.

Although freeze-drying has been a useful process for as much as fifty years now, its

commercial applications can be limited by high capital cost for a freeze-drying unit and

high operating costs for the vacuum, heater, and condenser.

REFERENCES:

1. The theory and practice of Industrial pharmacy by Leon.Lachmann and Herbert

A.Lieberman. Page no. 62-64, 672-674

2. Â¢ freeze drying for food products by J.M C N. Dalgleish. MJ: Freeze drying, in

Swarbrick J (ed): Encyclopedia of Pharmaceutical Technology, Informa

Healthcare, USA, Vol. 3, pp 1807-1833, 2007.

3. Pikal MJ: Freeze drying, in Swarbrick J (ed): Encyclopedia of Pharmaceutical

Technology, Informa Healthcare, USA, Vol. 3, pp 1807-1833, 2007 Jennings TA:

Effect of formulation on lyophilization, part 1. IVD Technology Magazine, 1997.

http://www.freezedryinginfo.com/FreezeDryers.html

4. The science and practice of pharmacy by Remington .21 st edition, vol.1.Pg 828-

831.

5. Dr. J. Jeff Schwegman (2009) "Basic Cycle Development Techniques for

Lyophilized Products".

http://www.freezedryinginfo.com/FreezeDryers.html

ISSN 0976-111X


6. 4.The Theory and Practice of Industrial Pharmacy – By Leon Lachman, Herbert

A. Lieberman, Joseph L. Kanic (THIRD EDITION) Remington.

www.wikipedia.com Lyophilization : compiled by Dr. Thanaset Senawong,

Biochemistry, Science KKU

7. Pikal MJ. Freeze-drying of proteins: process, formulation, and stability. ACS

Symposium Series. 1994;567:120–133. doi: 10.1021/bk-1994-0567.ch008.

8. Adams GDJ, Irons LI. Some implications of structural collapse during freeze-

drying using Erwinia caratovora l-asparaginase as a model. J Chem Biotechnol.

1993;58:71–76.

9. Rambhatla S, Pikal MJ. Heat and mass transfer scale-up issues during freeze-

drying, I: atypical radiation and the edge vial effect. AAPS PharmSciTech.

2003;4(2):111–120. doi: 10.1208/pt040214.

10. Pikal MJ, Roy ML, Shah S. Mass and heat transfer in vial freeze-drying of

pharmaceuticals: role of the vial. J Pharm Sci. 1984;73(9):1224–1237. doi:

10.1002/jps.2600730910.

11. Nail SL, Johnson W. Methodology for in-process determination of residual water

in freeze-dried products. Dev Biol Stand. 1992;74:137–151.

12. Roy ML, Pikal MJ. Process control in freeze drying: determination of the end

point of sublimation drying by an electronic moisture sensor. J Parenter Sci

Technol. 1989;43(2):60–66.

13. Gieseler H, Kessler WJ, Finson M, Davis SJ, Mulhall PA, Bons V, et al.

Evaluation of tunable diode laser absorption spectroscopy for in-process water

vapor mass flux measurements during freeze drying. J Pharm Sci.

2007;96(7):1776–1793. doi: 10.1002/jps.20827.

14. Mayeresse YVR, Sibille PH, Nomine C. Freeze-drying process monitoring using

a cold plasma ionization device. PDA J Pharm Sci Technol. 2007;61(3).

ISSN 0976-111X


15. Bardat A, Biguet J, Chatenet E, Courteille F. Moisture measurement: a new

method for monitoring freeze-drying cycles. J Parenter Sci Technol.

1993;47(6):293–299.

16. Tang X, Pikal MJ. Design of freeze-drying processes for pharmaceuticals:

practical advice. Pharm Res. 2004;21(2):191–200. doi:

10.1023/B:PHAM.0000016234.73023.75. [

17. Tang X, Nail SL, Pikal MJ. Freeze-drying process design by manometric

temperature measurement: design of a smart freeze-dryer. Pharm Res.

2005;22(4):685–700. doi: 10.1007/s11095-005-2501-2.

Date post:	15-Nov-2023
Category:	Documents
Upload:	independent
View:	0 times
Download:	0 times