Freeze Drying Report

B. Tech. Seminar (CHE)

A Seminar Report On

Title: FREEZE DRYING Name: Sanjana Bhattacharyya Roll Number: 115537 Copy for: Department

Date of submission: 5.02.2014

Department of Chemical Engineering Heritage Institute of Technology, Kolkata

A Seminar Report On

Title: FREEZE DRYING Name: Sanjana Bhattacharyya Roll Number: 115537 Copy for: Department

Date of submission: 5.02.2014

Department of Chemical Engineering Heritage Institute of Technology, Kolkata

Abstract

This report provides an overview of freeze drying (lyophilization) with particular relevance to pharmaceutical and food and industrial applications. The report discusses the phenomenon that is the foundation of freeze drying method and the specifics of the process involved. The comparison of both preservation processes, hot air and freeze-drying, was done taking into account several important characteristics such as shrinkage, glass transition temperature, process–quality interaction, drying kinetics, costs and new improvements. An updated bibliographic research served to compare both drying processes. Experimental data as well as theoretical results, from several years of research in the subject, were presented and compiled in order to support conclusions. Furthermore, the possible improvements have been stated as well. Keywords: freeze drying, lyophilization, freezing, food industry, pharmaceutical

Contents

1. Introduction

1

1.1 History

1

2. Basic principle

2

3. Freeze drying process

4

3.1 Pre-treatment

5

3.2 Freezing

5

3.3 Primary drying

7

3.4 Secondary drying

9

4. Freeze dryer

9

4.1 Rotary freeze dryer

10

4.2 Manifold freeze dryer

10

4.3 Tray style freeze dryer

10

5. Applications

11

5.1 Food industry

11

5.2 Pharmaceutical industry

14

5.3 Technological industry

15

5.4 Other applications

15

6. Possible improvements

16

7. Conclusion

17

List of figures

1. Phase diagram of water

3

2. Lyophilization cycle

4

3. Comparison of minimum chamber pressure as a function of drying rate

8

4. A freeze dried fruit platter retains flavor and texture well

12

5. Freeze dried and dehydrated fruits differ visibly in terms of texture and colour

14

6. Scanning Electron Microscopy (SEM) analysis of freeze dried pharmaceutical product

15

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1. Introduction Freeze drying, or lyophilization as it is referred to in the Pharmaceutical and Diagnostic Industries, is a dehydration technique, which enables liquid or slurry products, which have previously been frozen to be dried under a vacuum. In freeze drying, the water is frozen, followed by its removal from the sample, initially by sublimation (primary drying) and then by desorption (secondary drying). In this process, the moisture content of the product is reduced to such a low level that does not support biological growth or chemical reactions which gives the stability to the formulation. This technique is useful in formulation development of drugs which are thermolabile and/or unstable in aqueous medium. The applications of freeze drying are numerous, but it is generally employed when the requirements demand. It is employed in preservation of temperature sensitive products, particularly those of biological origin, such as enzymes, blood plasma, vaccines, etc. To achieve a chemical balance, such as for biological reagents or to provide a practical solution for certain delivery problems (for example, the packaging of constituents that cannot be mixed in the liquid state, but which are solidified in successive stages and then freeze dried), freeze drying is often used. This process has also found uses in implementation of an important stage of a product (to achieve a certain concentration) or in improvement storage life and improved marketing of the end product or in resolving certain filling problems. It may be difficult, for instance, to divide several milligrams of powder into precise vial dosages, due to the difficulty of measuring tiny amounts, homogeneity, granulation, static electricity etc. The distribution of the product from the liquid state eliminates such production problems.

1.1 History The basic process of freeze-drying food was known to the ancient Peruvian Incas of the Andes. Freeze-drying, or lyophilization, is the sublimation/removal of water content from frozen food. The dehydration occurs under a vacuum, with the plant/animal product solidly frozen during the process. Shrinkage is eliminated or minimized, and a near-perfect preservation results. Freeze-dried food lasts longer than other preserved food and is very light, which makes it perfect for space travel. The Incas stored their potatoes and other food crops on the mountain heights above Machu Picchu. The cold mountain temperatures froze

Page |2 the food and the water inside slowly vaporized under the low air pressure of the high altitudes. During World War II, the freeze-dried process was developed commercially when it was used to preserve blood plasma and penicillin. Freeze-drying requires the use of a special machine called a freeze-dryer, which has a large chamber for freezing and a vacuum pump for removing moisture. As the use of lyophilization expanded, the process began to be industrialized. Loire, Stokes, Edwards, and others designed and built the first equipment for the purpose. Called “lyophilization” by Flosdorf, the process faced its first major challenge under Sir Ernst Boris Chain, who used the technique to preserve antibiotics. Given Chain’s results turned to lyophilization to prepare vaccines and, later on, to refine blood fractions. By the mid-1950s, many industries were already using freeze drying to preserve pharmaceutical and biological products, as were the physicians and surgeons who developed tissue-banking for plastic and reconstructive surgery. Drs. Hyatt, Bassett, and Meryman of the United States Navy were among the early pioneers in the field. Over 400 different types of freeze-dried foods have been commercially produced since the 1960s. Two bad candidates for freezedrying are lettuce and watermelon because they have too high a water content and freeze-dry poorly. Freeze-dried coffee is the best-known freeze-dried product. There are several advantages of the freeze drying process to stabilize delicate products (e.g. proteins, peptides, etc.): Properly freeze dried products (1) do not need refrigeration, (2) can be stored at ambient temperatures, (3) can be completely reconstituted with water for injection (WFI) within seconds and (4) are stable over a 2 year shelf life. The drawback, however, is that freeze drying is an expensive process (long process times, limited throughput) and requires specialized equipment.

2. Basic Principle Lyophilization process is based on the principle of sublimation of ice, without entering the liquid phase. This phenomenon is seen in really cold and dry climes where the snow sublimating through a process that is similar to evaporation. Whenever there is an interface of air and water, either liquid or solid, you have molecules trying to leave the water. The constantly vibrating molecules in a liquid or solid are restrained by other forces, but a water

Page |3 molecule will escape the water and enter the air when it moves violently enough. It is called evaporation from a liquid, and sublimation from a solid. Sublimation is also obvious in the freezers, where the ice cubes tend to shrink with time. It is also visible in snowfields that eventually waste away without melting. It is noticed that there is no liquid water, none of the hard ice that results from melting and refreezing, but the snow still shrinks. Low relative humidity, as often found on cold days, speeds sublimation, and so does strong sunlight. Snow absorbs much of the near-infrared portion of sunlight , and that energy accelerates its water molecules, speeding sublimation.

Figure 1: Phase diagram of water

The phase diagram of water represents that two phases coexist along a line under the given conditions of temperature and pressure, while at the triple point (0.0075 ºC at 0.61 kPa or 610 Nm2; 0.01 ºC at 0.00603 atm), all three phases coexist. If water is cooled below 0 ºC and reheated, there are two possibilities. One under normal pressure, or above, it will turn into liquid. But, at sub-atmospheric pressures, more precisely, below 0.006 atm, there isn’t enough ambient pressure for water to liquefy. So it accepts the heat of sublimation and turns into vapour. This phenomenon is utilized by freeze drying. This process is performed at temperature and pressure conditions below the triple point, to facilitate sublimation of ice. The entire process is performed at low temperature and pressure, so that useful for drying of

Page |4 thermolabile compounds. Various important steps involved in lyophilization process which start from sample preparation followed by freezing, primary drying and secondary drying, to obtain the final dried product with desired moisture content.

Figure 2: Lyophilization cycle

The concentration gradient of water vapour between the drying front and condenser is the driving force for removal of water during lyophilization. The vapour pressure of water increases with an increase in temperature during the primary drying. Therefore, primary drying temperature should be kept as high as possible, but below the critical process temperature, to avoid a loss of cake structure. This critical process temperature is the collapse temperature for amorphous substance, or eutectic melt for the crystalline substance. During freezing, ice crystals start separating out until the solution becomes maximally concentrated. On further cooling, phase separation of the solute and ice takes place. If the solute separates out in crystalline form, it is known as the eutectic temperature. In contrast, if an amorphous form is formed, the temperature is referred to as the glass transition temperature. Determination of this critical temperature is important for development of an optimized lyophilization cycle. During primary drying, drying temperature should not exceed the critical temperature, which otherwise leads to ‘meltback’ or ‘collapse’ phenomenon in case of crystalline or amorphous substance respectively.

3. Freeze drying process A typical freeze-drying process consists of four important stages, that is, pre-treatment, freezing, primary drying, and secondary drying. In freezing, most of the solvent, typically water, is separated from the solutes to form ice. The freezing stage typically takes several hours to finish. Primary drying, or ice sublimation, begins whenever the chamber pressure is

Page |5 reduced and the shelf temperature is raised to supply the heat removed by ice sublimation. During primary drying, the chamber pressure is well below the vapour pressure of ice, and ice is transferred from the product to the condenser by sublimation and crystallization onto the cold coils/plates (