LYOPHILIZATION PROCESS - AN OVERVIEW

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ABOUT AUTHORS:
*Naveen Kamboj1, Sadanand Maurya2, Sonia Kamboj3, Gaurav kumar Singh2
1Chandigarh College of Pharmacy, Landran, Mohali, Panjab
2Transalam Institute of Pharmaceutical Education and Reaserch, Meerut, Uttar Pradesh
3ISF college of pharmacy moga, Punjab
*kamboj.naveen21@gmail.com

ABSTRACT
The most important method for developing the very stable and suitable formulation for thermolabile as well as thermostable drug is lyophilization which works on the principle of sublimation of ice crystal from frozen material. Principle of the process through the basis of formulation, freezing, primary drying and secondary drying . In order to design optimum lyophilization process, process development scientific need to the critical properties of the formulation and how to apply to this information to process design. Lyophilized formulation not only has the advantage of better stability, but also provide easy handling i.e. shipping and storage. This article present an overview of lyophilization process, its advantage and pharmaceutical application.


REFERENCE ID: PHARMATUTOR-ART-1844

FREEZE DRYING TECHNOLOGY
Historical Overview

Drying from the frozen state is not uncommon in nature. In the winter, snow vanishes along the roads in dry cold air without melting. In Central Siberia, scientists have found the large bodies of mammoths that have been progressively freeze-dried during the past 15,000 years. In the Peruvian high plateau, the Incas reportedly stored, in their tambos, meat that had been dried in the sun at the reduced pressure of the Andes Scientific interest in freeze-drying began at the turn of the twentieth century with a publication by Bordas and d'Arsonval at the French Academy of Sciences. Following that publication, Altman and later Gersh used this technique to prepare undistorted dry samples for microscopy. Ronald Greaves, in Cambridge, UK, began his work along those lines in the 1930s by preparing dry suspensions of living bacteria. However, this technique still was only familiar to a handful of scientists in isolated laboratories.  

Then came World War II. With tens of thousands of casualties on the battlefields, human plasma was in great need, and freeze-drying again entered the limelight. Thanks to Greaves in England, François Henaff in France, and Earl Flosdorf in the United States, thousands of liters of blood were processed to isolate plasma, which was then preserved by freezing and drying. 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.1,2  


INTRODUCTION
In Lyophilization, or freeze drying, there is a 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 useful in formulation development of drugs which are thermolabile and/or unstable in aqueous medium.3,4,5

Lyophilization process is based on the principle of sublimation of ice, without entering the liquid phase. The phase diagram of water (Figure 1) represent  that two phases coexist along a line under the given conditions of temperature and pressure, while at the triple point (0.0075 ?C at 0.61kPa or 610 Nm-2; 0.01 ?C at 0.00603 atm), all three phases coexist.


Figure 1- Phase diagram showing the triple point of water at 0.01°C, 0.00603 atm. Lyophilization is take place below the triple point.

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 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).


Figure 2.  importantSteps involved in lyophilization process from sample preparation to final product formation. Annealing is an another optional step, occasionally used to crystalline substance.

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 structure6,7,8. This critical process temperature is the collapse temperature for amorphous substance, or eutectic melt for the crystalline substance1,9,10.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 (Tg’).

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 (Figure 3).11


Figure 3 Flowchart showing the concept of eutectic temperature and Tg, and their importance during primary drying

ADVANTAGES-
Lyophilization process has various important advantages compared to other drying and preserving techniques.12

1-It is a ideal drying technique for heat sensitive products,

2-It can be stored at ambient temperature over a 2 year shelf life, enhanced product stability in a dry state.

3- Easy reconstitution greatly reduces weight and makes the products easier to transport, maintains food/biochemical and chemical reagent quality.

4- Reconstitution of the dried product facilitates use in emergency medicine and safe application in hospitals.

5- It is not limited to products for parenteral use, but can also be used for fast dissolving sublingual tablets. Tablets can    have very low disintegration time and have great mouth feel due to fast melting effect.  

6-it is much easier to achieve sterility assurance and freedom of particles than using other drying methods or handling of dry powders.

7-lyophilized products sensitive to oxidation can be stoppered and sealed within an inert atmosphere (i.e. nitrogen) to minimize detrimental effects.

DISADVANTAGES-
Although lyophilization has many advantages compared to other drying and preserving techniques it has quite a few disadvantages. It is a long and cost intensive process, requires sterile diluents for reconstitution, it should only be used when product is unstable and heat-liable and the limited amount of vials processed in each run restricts the overall production capacity. 12

MATERIAL THAT CAN BE LYOPHILIZED-
The major type of material that can be lyophilized summarized bellow-12
1-Non-living bio products this comprises the major areas of application and include:

  • Enzyme, hormones, antibiotics, vitamins, blood products, inactivated vaccines etc.
  • Foodstuffs where organoleptic  properties are important
  • Industrially useful bio-products.
  • Bone and other body tissue for medical and surgical use.

2-Non-biological where the process is used to dehydrate and concentrate reactive and heat labile chemicals.

3- Living organism- where reconstituted cells after drying must be able to grow and multiply to produce new progency.

4- miscellaneous- Flood damaged books, museum, artifacts etc.

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