ASSIGNMENT OF PHYSICAL

PHARMACY
SUBMITTED TO
MAM FATIMA NASEEM
GROUP 1
HAMZA GUL
MUHAMMAD ABDULLAH UMAR
MUHAMMAD ALI
LARAIB EJAZ
ALISHBA
MAHEEN IFTIKHAR
 LYOPHILIZATION
Freeze drying, also known as lyophilization or cryodesiccation, is a low temperature dehydration
process that involves freezing the product and lowering pressure, removing the ice
by sublimation This is in contrast to dehydration by most conventional methods that evaporate water
using heat.
Because of the low temperature used in processing, the rehydrated product retains much of its
original qualities. When solid objects like strawberries are freeze dried the original shape of the
product is maintained. If the product to be dried is a liquid, as often seen in pharmaceutical
applications, the properties of the final product are optimized by the combination of excipients (i.e.,
inactive ingredients). Primary applications of freeze drying include biological (e.g., bacteria and
yeasts), biomedical (e.g., surgical transplants), food processing (e.g., coffee) and preservation.

Stages of freeze drying OR lyophilization

There are four stages in the complete freeze drying process: pretreatment, freezing, primary drying,
and secondary drying.

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,
preserve appearance, and/or improve processing), decreasing a high-vapor-pressure solvent, or
increasing the surface area. Food pieces are often IQF treated to make them free flowing prior to
freeze drying. Freeze dried pharmaceutical products are in most cases parenterals administered
after reconstitution by injection which need to be sterile as well as free of impurity particles. Pre-
treatment in these cases consists of solution preparation followed by a multi-step filtration.
Afterwards the liquid is filled under sterile conditions into the final containers which in production
scale freeze dryers are loaded automatically to the shelves.
In many instances the decision to pretreat a product is based on theoretical knowledge of freeze-
drying and its requirements, or is demanded by cycle time or product quality considerations

Freezing and annealing

During the freezing stage, the material is cooled below its triple point, the temperature at which the
solid, liquid, and gas phases of the material can coexist. This ensures that sublimation rather than
melting will occur in the following steps. To facilitate faster and more efficient freeze drying, larger
ice crystals are preferable. The large ice crystals form a network within the product which promotes
faster removal of water vapor during sublimation.[2] To produce larger crystals, the product should be
frozen slowly or can be cycled up and down in temperature in a process called annealing. The
freezing phase is the most critical in the whole freeze-drying process, as the freezing method can
impact the speed of reconstitution, duration of freeze-drying cycle, product stability, and appropriate
crystallization.
Amorphous materials do not have a eutectic point, but they do have a critical point, below which the
product must be maintained to prevent melt-back or collapse during primary and secondary drying.
Structurally sensitive goods
In the case of goods where preservation of structure is required, like food or objects with formerly-
living cells, large ice crystals will break the cell walls which can result in increasingly poor texture
and loss of nutritive content. In this case, the freezing is done rapidly, in order to lower the material
to below its eutectic point quickly, thus avoiding the formation of large ice crystals. Usually, the
freezing temperatures are between −50 °C (−58 °F) and −80 °C (−112 °F).

Primary drying
During the primary drying phase, the pressure is lowered (to the range of a few millibars),
and enough heat is supplied to the material for the ice to sublimate. The amount of heat
necessary can be calculated using the sublimating molecules' latent heat of sublimation. In
this initial drying phase, about 95% of the water in the material is sublimated. This phase may
be slow (can be several days in the industry), because, if too much heat is added, the
material's structure could be altered.
In this phase, pressure is controlled through the application of partial vacuum. The vacuum speeds
up the sublimation, making it useful as a deliberate drying process. Furthermore, a cold condenser
chamber and/or condenser plates provide a surface(s) for the water vapour to re-liquify and solidify
on.
It is important to note that, in this range of pressure, the heat is brought mainly by conduction or
radiation; the convection effect is negligible, due to the low air density.

Secondary drying:

A benchtop manifold freeze-drier

The secondary drying phase aims to remove unfrozen water molecules, since the ice was removed
in the primary drying phase. This part of the freeze-drying process is governed by the
material's adsorption isotherms. In this phase, the temperature is raised higher than in the primary
drying phase, and can even be above 0 °C (32 °F), to break any physico-chemical interactions that
have formed between the water molecules and the frozen material. Usually the pressure is also
lowered in this stage to encourage desorption (typically in the range of microbars, or fractions of
a pascal). However, there are products that benefit from increased pressure as well.
After the freeze-drying process is complete, the vacuum is usually broken with an inert gas, such as
nitrogen, before the material is sealed.
At the end of the operation, the final residual water content in the product is extremely low, around
1–4%.

Applications of freeze drying

reeze-drying causes less damage to the substance than other dehydration methods using higher
temperatures. Nutrient factors that are sensitive to heat are lost less in the process as compared to
the processes incorporating heat treatment for drying purposes. 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.

Pharmaceuticals and biotechnology

Pharmaceutical companies often use freeze-drying to increase the shelf life of the products, such as
live virus vaccines, biologics and other injectables. By removing the water from the material and
sealing the material in a glass vial, the material can be easily stored, shipped, and later reconstituted
to its original form for injection. Another example from the pharmaceutical industry is the use of
freeze drying to produce tablets or wafers, the advantage of which is less excipient as well as a
rapidly absorbed and easily administered dosage form.
Freeze-dried pharmaceutical products are produced as lyophilized powders for reconstitution in vials
and more recently in prefilled syringes for self-administration by a patient.
Examples of lyophilized biological products include many vaccines such as live measles virus
vaccine, typhoid vaccine, and meningococcal polysaccharide vaccine groups A and C combined.
Other freeze-dried biological products include antihemophilic factor VIII, interferon alfa , anti-blood
clot medicine streptokinase, and wasp venom allergenic extract.
Many bio-pharmaceutical products based on therapeutic proteins such as monoclonal antibodies
require lyophilization for stability. Examples of lyophilized biopharmaceuticals include blockbuster
drugs such as etanercept (Enbrel by Amgen), infliximab (Remicade by Janssen Biotech), rituximab,
and trastuzumab (Herceptin by Genentech).
Cell extracts that support cell-free biotechnology applications such as point-of-care diagnostics and
biomanufacturing are also freeze-dried to improve stability under room temperature storage.[16][17]
Dry powders of probiotics are often produced by bulk freeze-drying of live microorganisms such
as lactic acid bacteria and bifidobacteria .

Freeze drying of food

Freeze dried bacon bars

Freeze-dried coffee, a form of instant coffee

Freeze-dried Bulgarian apricot, melon, meatball soup, tarator

Freeze dried ice cream and chocolate, and spaghetti with bacon

The primary purpose of freeze drying within the food industry is to extend the shelf-life of the food
while maintaining the quality. Freeze-drying is known to result in the highest quality of foods
amongst all drying techniques because structural integrity is maintained along with preservation of
flavors.[1] Because freeze drying is expensive, it is used mainly with high-value products. Examples
of high-value freeze-dried products are seasonal fruits and vegetables because of their limited
availability, coffee; and foods used for military rations, astronauts/cosmonauts, and/or hikers.
NASA and military rations
Because of its light weight per volume of reconstituted food, freeze-dried products are popular and
convenient for hikers, as military rations, or astronaut meals. A greater amount of dried food can be
carried compared to the same weight of wet food. In replacement of wet food, freeze dried food can
easily be rehydrated with water if desired and shelf-life of the dried product is longer than fresh/wet
product making it ideal for long trips taken by hikers, military personnel, or astronauts. The
development of freeze drying increased meal and snack variety to include items like shrimp cocktail,
chicken and vegetables, butterscotch pudding, and apple sauce.
Fruits :
With conventional dehydration, berries can degrade in quality as their structure is very delicate and
contains high levels of moisture. Strawberries were found to have the highest quality when freeze
dried; retaining color, flavour, and ability to be re-hydrated.

Advantages:
Freeze-drying is viewed as the optimal method of choice for dehydration of food because of the
preservation of quality, meaning characteristics of the food product such as aroma, rehydration, and
bioactivity, are noticeably higher compared to foods dried using other techniques.

Shelf-life extension:
Shelf-life extension results from low processing temperatures in conjunction with rapid transition of
water through sublimation.With these processing conditions, deterioration reactions, including
nonenzymic browning, enzymatic browning, and protein denaturation, are minimized. When the
product is successfully dried, packaged properly, and placed in ideal storage conditions the foods
have a shelf life of greater than 12 months.

Re-hydration:
If a dried product cannot be easily or fully re-hydrated, it is considered to be of lower quality.
Because the final freeze dried product is porous, complete re-hydration can occur in the food. This
signifies greater quality of the product and makes it ideal for ready-to-eat instant meals.

Effect on nutrients and sensory quality:

Due to the low processing temperatures and the minimization of deterioration reactions, nutrients are
retained and color is maintained. Freeze-dried fruit maintains its original shape and has a
characteristic soft crispy texture.

Disadvantages
Microbial growth:
Since the main method of microbial decontamination for freeze drying is the low temperature
dehydration process, spoilage organisms and pathogens resistant to these conditions can remain in
the product. Although microbial growth is inhibited by the low moisture conditions, it can still survive
in the food product. An example of this is a viral hepatitis A outbreak that occurred in the United
States in 2016, associated with frozen strawberries. If the product is not properly packaged and/or
stored, the product can absorb moisture, allowing the once inhibited pathogens to begin reproducing
as well.

Cost:
Freeze-drying costs about five times as much as conventional drying, so it is most suitable for
products which increase in value with processing. Costs are also variable depending on the product,
the packaging material, processing capacity, etc.[ The most energy-intensive step is sublimation.

Silicone oil leakage

Silicone oil is the common fluid that is used to heat or cool shelves in the freeze-dryer. The
continuous heat/cool cycle can lead to a leakage of silicone oil at weak areas that connect the shelf
and hose. This can contaminate the product leading to major losses of pharmaceuticals and food
products. Hence, to avoid this issue, mass spectrometers are used to identify vapors released by
silicone oil to immediately take corrective action and prevent contamination of the product.

Products:
Mammalian cells generally do not survive freeze drying even though they still can be preserved.

Equipment and types of freeze dryers:

Unloading trays of freeze-dried material from a small cabinet-type freeze-dryer

A residential freeze-dryer, along with the vacuum pump, and a cooling fan for the pump

There are many types of freeze-dryers available, however, they usually contain a few essential
components. These are a vacuum chamber, shelves, process condenser, shelf-fluid system,
refrigeration system, vacuum system, and control system.

Function of essential components

Chamber
The chamber is highly polished and contains insulation, internally. It is manufactured with stainless
steel and contains multiple shelves for holding the product. A hydraulic or electric motor is in place
to ensure the door is vacuum-tight when closed.
Process condenser
The process condenser consists of refrigerated coils or plates that can be external or internal to the
chamber. During the drying process, the condenser traps water. For increased efficiency, the
condenser temperature should be 20 °C (36°F) less than the product during primary drying and have
a defrosting mechanism to ensure that the maximum amount of water vapor in the air is condensed.
Shelf fluid
The amount of heat energy needed at times of the primary and secondary drying phase is regulated
by an external heat exchanger. Usually, silicone oil is circulated around the system with a pump.
Refrigeration system
This system works to cool shelves and the process condenser by using compressors or liquid
nitrogen, which will supply energy necessary for the product to freeze.
Vacuum system
During the drying process, a vacuum of 50–100 microbar is applied, by the vacuum system, to
remove the solvent. A two-stage rotary vacuum pump is used, however, if the chamber is large then
multiple pumps are needed. This system compresses non-condensable gases through the
condenser.
Control system
Finally, the control system sets up controlled values for shelf temperature, pressure and time that
are dependent on the product and/or the process.The freeze-dryer can run for a few hours or days
depending on the product

References

1: Ratti, Cristina (2008-11-21). Advances in Food Dehydration. CRC Press. pp. 209–
235. ISBN 9781420052534.
2: Fellows, P. (Peter) (2017). "Freeze drying and freeze concentration". Food processing technology :
principles and practice (4th ed.). Kent: Woodhead Publishing/Elsevier Science. pp. 929–940. ISBN 978-
0081005231. OCLC 960758611
3: Prosapio, Valentina; Norton, Ian; De Marco, Iolanda (2017-12-01). "Optimization of freeze-drying using a
Life Cycle Assessment approach: Strawberries' case study" (PDF). Journal of Cleaner Production. 168: 1171–
1179. doi:10.1016/j.jclepro.2017.09.125. ISSN 0959-6526.
4: atti, C (2001). "Hot air and freeze-drying of high-value foods: a review". Journal of Food Engineering. 49 (4):
311–319. doi:10.1016/s0260-8774(00)00228-4.