Download Chapter 7 Freeze Drying of Pharmaceuticals

Chapter 7 Freeze Drying of
Pharmaceuticals
7.1 Basic issues for pharmaceutical
freeze-drying
• 7.1.1 New Dosage forms of pharmaceutical drugs
• According to its development, pharmaceutical dosage
form can be divided into the following generations：
– The first generation : simple ointment, pill and powder for oral
administration and external use.
– The second generation: the tablets, injections, capsules and
aerosols made by mechanical and automatic machines.
– The third generation: slow-release or controlled-release dosage
forms that form a new drug delivery system (DDS) .
– The fourth generation:targeted dosage forms that form a targeted
drug delivery system.
– The fifth generation: the automatic release dosage forms inside the
body when the patients have a serious illness.
• At present, the third and fourth generations of dosage
forms are most concerned by scientists.
• In order to realize these new drug delivery
system, many new techniques are
developed in the formulation of dosage
form, such as
– solid dispersion,
– inclusion,
– emulsion,
– liposomes,
– microencapsulation.
7.1.2 Biological drugs
1. Definition and classification of Biological drugs
• Drugs can be divided into three categories:
– chemical drugs (or synthetic drugs);
– biological drugs;
• are bioactivative preparations that are made from a
living organism, parasites, animal toxins or their
products and are used in the prevention, diagnosis,
or treatment of cancer and other diseases.
– natural drugs (Chinese medicine)
• Biological drugs include
– antibodies, interleukins, and vaccines.
• Biological drugs can be classified according to
– the raw materials, biological or separation technology,
or their clinical use.
• According to biological technology, biological
drugs can be divided into four categories
– Drugs produced by fermentation methods.
• Drugs are produced by microbial metabolism,
• including antibiotics, vitamins, organic acids, coenzymes,
enzyme inhibitors, hormone, immunomodifier, as well as
other physiologically active substances.
– Drugs produced by genetic methods.
• Protein and polypeptide-type drugs are produced by
recombinant DNA,
• including interferon, insulin, interleukin-2 and so on.
– Drugs produced by cell engineering.
• Drugs are produced by cell culture of botanical and
zoic cells,
• such as human physiological active factors,
vaccine, monoclonal antibody, and so on;
– Drugs produced by enzyme engineering.
• They include medicinal enzyme and drugs which
produced by enzyme or cells immobilization,
• such as protease, urgency enzyme, Lasparaginase, vitamin C, and so on.
2. Characteristics of biological drugs
• Biological drugs have some distinct
characteristics:
– The components are too complex to be measured
accurately.
– Because the drugs are composed by a variety of
protein that is active, they are affected by temperature.
• They are unstable and susceptible to denaturation and
deactivation.
• The changes of parameters in production process have great
influence on the quality of products .
– they are susceptible to been polluted and destructed
by microorganism.
7.1.3 Basic process of biological drugs freezedrying
• The technical procedures of drug freeze-drying
consist of four processes:
–
–
–
–
preparation and freezing,
primary drying (sublimation drying),
secondary drying (desorption drying)
package.
• The temperature, vacuum for each process have
to be controlled precisely.
• The freeze-dried drugs are dry and porous
solids.
– They can be stored in room temperature or in
refrigerator for a long time.
• 1. Preparation and freezing of drugs
– In order to form a stable porous structure after freeze drying, the
concentration of drug solution must be a specific value.
– Excipients should be added into the low dose thermal sensitive
drugs (hormone, enzyme, vaccine) to reinforce the structure of
freeze-dried products.
– Lyoprotectant should be added into the biological protein-type
drugs or slow-release drugs with bio-membrane to protect
proteins from denaturation and the bio-membrane from damage.
– The end temperature of pre-freezing must be lower than the
glass transition temperature (Tg) or eutectic temperature (Te) of
the drug solution.
• 2. Primary drying (sublimation drying)
– are performed at low temperature and vacuum.
– The drying progresses gradually from the surface to the
center of the products.
– The pores or channels formed by the sublimation ice
become the ways of vapor to escape.
– The boundary between drying layer and frozen layer is
known as the sublimation interface.
– The temperature of the sublimation interface is a critical
parameter to be controlled in primary drying process.
– 90% water in drugs is removed after primary drying.
– In primary drying process, the temperature of frozen
layer must be lower than Te or Tg’.
– The temperature of dried layer must is lower than the
collapse temperature (Tc).
– The temperature of the heater in the drying chamber
should be controlled strictly.
• 3. Secondary drying (desorption drying)
– purpose : to remove a portion of the bound water.
• The moisture content of drugs is lower than 3% after
secondary drying.
– Because of large absorption energy, the product
temperature in secondary drying must be
increased high enough to remove the bound water,
and on the other hand, this temperature cannot
induce denaturation of proteins and deterioration
of biological drugs.
• The Tg of the products increases gradually with the
decrement of water in secondary process.
• So the drying temperature of the products can be
increased gradually, but cannot be higher than Tg.
• 4. Encapsulation process
– When the secondary drying process is complete,
plugging system in the chamber is used directly
to plug the vials in order to prevent the freeze
dried drugs from oxidation and water absorption.
– The encapsulation can also be completed after
filling nitrogen gas into the chamber.
7.1.4 Characteristics of freeze-drying
technology for drugs
• characteristics of freeze-drying technology
for drugs are
– can prevent the active components in from
denaturation or loss of biological activity.
– can protect the components in drugs from oxidation.
– can greatly reduce the loss of volatile components in
drugs.
– can inhibit the growth of microorganism and the
activity of enzyme in drugs.
– Freeze dried drugs will maintain the original structure.
– Freeze dried drugs have good rehydration property.
– Freeze dried drugs can be stored at room
temperature for a long time
– The initial cost of freeze-drying equipment is larger.
Freeze drying is a time and energy consuming
process.
– It is very difficult to control the parameters at optimum
level.
7.1.5 Critical problems of freeze-drying in drugs
• 1. Temperature Control and
identification of drying procedures
– Frozen drugs will melt, collapse or crimple if the
temperature is higher than the optimum temperature.
– if the temperature is too low, refrigeration load will causing
excessive energy consumption and the sublimation rate will
be decreased greatly
• 2. Cooling Rate in freezing process
– freezing process determines the drying rate
and the quality of freeze-dried product.
– The optimum cooling rates vary with different
biological agents.For instance,
• slow freezing is usually beneficial to protein
polypeptide-type drugs.
• Fast freezing is usually beneficial to the virus and
vaccine.
• 3. Types and concentration of
lyoprotectant
– The molecular structure of the active components
is different for different biological agents.
– The types and concentration of lyoprotectants
required in freeze drying are also different.
– Up to now, there is not a universal lyoprotectant
applied to all of the biological agents.
7.2 Freeze-drying of Protein and
Hormone
• Bio-protein-type drugs
– are typical products of modern bioengineering
preparation.
– easy to be polymerized in liquid state because
they are thermal sensitive.
– easy to be contaminated microorganism and
oxidized when exposed in air.
– Freeze drying is an effective technique for the
storage of bio-protein-type drugs.
7.2.1 Freeze-drying of enzyme
• Almost all enzymes are proteins that catalyze chemical
reactions
• Example: Cu/Zn SOD
7.2.2 Interleukin
• Cytokine or growth factors are polypeptides used to
regulate cellular proliferation and differentiation.
• Cytokine related to immunization is called interleukin
• Example:
7.3 Freeze drying of fibrinogen
• 7.3.1 Fibrin Glue (also called fibrin
sealant, FS)
– The properties of fibrin glue (also called fibrin sealant, FS) are
better than any other biological or synthetic surgical hemostat in
aspect of histocompatibility, nontoxicity and clinical efficacy.
7.3.2 Fibrinogen
• Fibrinogen is one of the two components of fibrin glue
• In clinic the freeze-dried fibrinogen are required to
rehydrate fast and to be stable in storage.
• Fibrinogen is a water-soluble active protein. It is unstable
in liquid state, easily deteriorated by oxidation.
7.3.3 The freeze-drying of fibrinogen
• 1. Fibrinogen preparation
– Plasma Preparation
– Extraction of fibrinogen
• 2. The temperature protocol for the freeze-drying of
fibrinogen
– Example:Freeze-dryer (Lyo-7.5)
• Thermocouples are placed inside the vials on the tray as shown in
Fig.7-3
• 3. Lyoprotectant for the freeze-drying of Fibrinogen
• Sucrose, glycine and mannitol are combined to formulate the
lyoprotectant.
• 4. The rehydration property and stability of freeze dried
fibrinogen
• see Table 7-1.
• The end