This is the most
suitable route of administration of drugs in treating patients who are
non-cooperative, unconscious or are otherwise unable to take the medicine
orally.
DISADVANTAGES OF
PARENTERAL PRODUCTS:
- It is expensive.
- People may have fear about the injectable
syringes.
- These products must be maintained strictly
t keep them sterile.
- Specialized equipment as well as trained
persons is needed for their administration.
- These may be painful after administration.
- Application through wrong routs may prove
fats.
- Daily or frequent administration of
injections may pose difficulties to the patient.
Intra-cutaneous or
Intra-dermal Injections:
These injections are
given in between dermis and epidermis. Skin of the left forearm is usually
selected for giving the injection.
Usually small volume,
from 0.1 to 0.2 ml can be injected by this route.
Mainly used for
testing the sensitivity of the injectables and for diagnostic purposes.
Sub-cutaneous or
Hypodermic Injections:
These injections are
given in the sub-cutaneous tissue under the skin of the upper arm. Normally
vaccine is injected into this route.
The volume of 1 ml or
less can be injected by this route.
Aqueous suspensions
and Oily suspensions & fluids cannot be injected by this route
Most popular route
because it is convenient for the patient and the doctor.
Intra-muscular
Injections:
These injections are
given into the muscular tissues of the shoulder, thigh or buttock.
Generally volume up
to 2 ml is administered by this route and should not exceed 5 ml at one site.
Specially 5 ml for gluteal region and 2ml for deltoid region are referred.
Intravenous
Injections:
Large volume of
solutions ranging from 1 to 500 ml or even more can be injected but volumes of
more than 1.5 ml should be isotonic with blood.
These injections are
given into the vein therefore directly reach the blood stream. The median
basilic vein is usually selected because it is easily located and connects with
the other major veins of the arm.
Oily injections and
suspensions cannot be injected by this route.
Intra-arterial
Injections:
These injections are
given directly into the artery for an immediate effect in a peripheral area.
But they are occasionally used. (eg. Tolazoline hydrochloride.)
Generally 10 ml can
be injected by this route.
Intra-cardiac
Injections:
They are given
directly into the heart muscles or ventricle. (eg. Adrenaline or isoprenaline
sulphate.)
This route is used in
emergency only.
Intrathecal
Injections:
They are given into
the subarachnoid space surrounding the spinal cord.
This route is used
for giving spinal anaesthesia (Bupivacaine) and antibiotics (streptomycin in
the treatment of tubercular meningitis.)
Intracisternal
Injections:
They are given in
between the first and second cervical vertebrae.
This route is
principally used to withdraw cerebrospinal fluid for diagnostic purposes and
occasionally used for antibiotic treatment.
Peridural Injections:
These injections are
given between the duramater and the inner aspects of the vertebra.
This route is
sometimes used for giving spinal anesthetics in special cases.
Intra-articular
Injections: These injections are given into the synovial fluid that lubricates
the articulating ends of bones in a joint.
Intracerebral
Injections: These injections are given into the cerebrum.
OFFICIAL TYPES OF
INJECTIONS:
Parenteral
preparations are classified by the USP and NF according to the following five
classifications:
Solutions, suspension
or emulsion of medicaments suitable for injection, referred to by titles of the
form “-------------- injection”.
Example: Insulin
injection, USP. Morphine injection USP.
Dry solids or liquid
concentrates containing no buffers, dilutes or other added substances and which
upon the addition of suitable solvents yields solutions conforming in all
respects to the requirements for injections and which are distinguished by
titles of the form “sterile-------------”.
Example: Sterile Chloramphenicol
Sodium Succinate, USP. Sterile Ampicillin Sodium, USP.
Again the above type
of preparations when contains one or more buffers, diluents or other added
substances it is defined by title of the form “----------------- for
injection.”
Example: Sodium
Thiopental for injection, USP. Methicillin Sodium for injection, USP.
Solids which are
suspended in a suitable fluid medium and which are not to be injected
intravenously or into the spinal canal distinguished by the title of the form
“sterile ------------- suspensions”.
Example: Sterile
Cortisol Suspension, USP. Sterile Epinephrine Suspension, USP.
Dry solids which upon
the addition of suitable vehicles yields preparations conforming in all
respects to the requirements for sterile suspensions, which are distinguished
by titles of the form, “sterile ----------- for suspensions.”
Example: Sterile
Chloramphenicol for Suspension, USP. Sterile Ampicillin for Suspension, USP.
Emulsions of fluids
in fluid media, suitable for parenteral administration, which are not to be
injected into the spinal canal and which are distinguished by titles of the
form “sterile ------------------ emulsions.”
Example: Sterile
Phytonadione Emulsions, USP.
DIFFERENCE BETWEEN
THE INJECTIONS AND ORAL PREPARATIONS:
The solutions and
suspensions of drugs intended for injection are prepared in the same general
manner as for oral solutions and suspensions with the following differences:
Solvents or vehicles
used must meet special purity and other standards assuring their safety by
injection.
The added substances
like buffers, stabilizers and antimicrobial preservatives should fulfill the
specific guidelines of use and restricted in certain parenteral preparations.
The use of coloring
agents is strictly prohibited.
Parenteral
preparations are always sterilized & meet sterility standards and must be
pyrogens free.
Parenteral solutions
must meet compendial standards for particular matter.
Parenteral products
must be prepared in environmentally controlled areas, under strict sanitation
standards.
Parenteral products
must be prepared by specially trained personnel and clothed to maintain the
sanitation standards.
Parenteral products
are packaged in special hermetic containers of specific and high quality.
Each container of an
injection is filled to a volume in slight excess of the labeled “size” or
volume to be withdrawn.
There are
restrictions over the volume of injection permitted in multiple-dose containers
and also a limitation over the types of containers which may be used for
certain injections.
Specific labeling
regulations apply to injections.
Sterile powders
intended for solution or suspension immediately prior to injection is
frequently packaged as lyophilized or freeze-dried. Powders to permit ease of
solution or suspension upon the addition of the solvent or vehicles.
The following factors
must be considered for the preparation of parenteral products:
Volume of injection.
Stabilizer.
Adjustment of PH.
Preservatives.
Adjustment of
specific gravity.
Adjustment of
isotonicity.
Vehicles.
Volume of injection:
The volume of
injection primarily depends on: ---
The solubility of the
medicaments.
The particular route
of administration. (eg. Intracutaneous injection have to be small other than IV
route is suitable for large volume.)
The volume should be
convenient to administer, like: volume greater than 20ml is unsuitable for
injection by a syringe. For dispensing a hypertonic solution, the volume can
often be reduced and administered by slow IV infusion.
Adjustment of PH:
The PH of many
official preparations is adjusted to a definite PH or to within a PH range. The
PH of a completed injection can be altered by: -------
The decomposition of
the medicament.
Leaching of alkali
from the glass container.
Extraction of acid or
alkaline impurities from the rubber closure.
Dissolving of gases
and vapors from the airspace in the container.
Thus adjustment of PH
is very necessary for parenteral preparation. Some of the reasons for PH
adjustment are as follows:
To increase the
stability of the injection: The optimal stability may prove a suitable
formulation. As unfavorable PH is one of the major causes of instability in
pharmaceuticals preparations. Thus adjustment of PH to the optimum plays a
vital role for maximum stability.
Eg.
PH
Alkaloids
(Ergometrine injections)
2.7-3.5
Vitamin
(Cyanocobalamin)
Polypeptides
(Oxytocin)
4.0-5.5
3.0-4.5
To minimize pain,
irritation and necrosis: Since for subcutaneous and IM routes, very acid or
alkaline solutions are painful on injection and may cause irritation or even
necrosis of the tissue. On the other hand, non-neutral solutions can cause
aseptic meningitis in Intrathecal, Peridural and Intracisternal routes. Thus
adjustment of PH between the ranges of 7.0-7.6, ideally PH 7.4 should be
maintained.
To provide
unsatisfactory conditions for growth of micro-organisms: Use of low and high PH
prevents the growth of micro-organisms. Solutions of PH below 4 are
bactericidal for many micro-organism and many not require additional protection
against bacteria. Example: Ethanolamine Injection does not contain any
bactericidal in multiple-dose containers for its anti-bacterial activities due
to its high PH of 8-9.
To enhance
physiological activity: Maximum physiological activity is shown by neutral or
alkaline solution if maximum stability is found in acidic PH. Thus PH should be
kept as high as physiologically possible with an acceptance level of stability.
Generally, in most cases, the biologic effectiveness of the drug is maximum at
or near the biologic fluid PH rather than at the stabilizing PH of the injected
products. Example: Procaine and Adrenaline solution produce the greatest
anaesthetic effect than its salts.
To help detect
decomposition: Decomposition of a medicament in solution is often accompanied
by a PH change. Thus PH change can be used to detect deterioration when
physical observation in storage condition, according to pharmacopoeia, is
failed such as protection from light and refrigeration.
Buffers: Buffers
systems are added to maintain a required PH for many products. Buffers systems
must be selected with consideration of their: ------
Effective range.
Concentration and
Chemical effect on
the total product.
Buffers systems
suitable for injections: -----
Should have no
toxicity.
Be compatible with
the medicaments.
Be compatible with
the excipients.
Should have a high
buffer capacity.
Example:
Citric
acid/Na-phosphate (Digixin Injection B.P)
Na-acetate (Insulin
Zinc suspension Injection B.P)
Na-phosphate
(Isophane Insulin Injection B.P)
Adjustment of
specific gravity:
For injection, the
specific gravity of the solution must be made carefully. Adjustment of specific
gravity plays a vital role in spinal anaesthesia. The specific gravity of
solution in relation to that of the C.S.F is isobaric, hypobaric and hyperbaric
i.e. of equal, lower and higher specific gravity respectly. Example:
Cinchocaine HCl 1 in 1500 in 0.5% saline is hypobaric and cinchocaine HCl 1 in
200 in 6% dextrose is a hyperbaric solution.
Adjustment of
isotonicity:
Tonicity refers to
the tone of a solution and is directly related to the osmotic pressure exerted
by the solution. Isotonic solution exerts the same osmotic pressure as blood or
0.9% NaCl solution. Hypertonics have a greater osmotic pressure than blood or
0.9% NaCl solutions. Hypotonic solutions have a lower osmotic pressure than
blood or 0.9% NaCl solution. Isotonicity actually depends on the permeability
of a living semi-permeable membrane that separates the solution from a biologic
cell system.
For Intravenous
Injections: Approximate isotonicity is always desirable. All hypotonic
solutions should be rendered isotonic, because administration may lead to pain
and hemolysis due to expand the cell. Hypertonic solutions are administered
through a central rather than peripheral vein to avoid pain caused by RBC
shrinkage. For diagnostic purpose, hypertonic solution is used for sclerosing
varicose veins. Example: Morrhuate Na Injection U.S.P, Ethanolamine Oleate
Injection B.P.
For Subcutaneous
Injections: The injection volume is very small and injected directly into fatty
tissue. So isotonicity is desirable but no essential. Other hand a wide range
of Para-tonicity is possible without unwanted effects.
For Intramuscular
Injections: The osmotic pressure will vary according to the type of Injection
and its desired therapeutic use. Aqueous solution should be slightly hypertonic
to promote rapid absorption. Aqueous depot formulation should be isotonic. A
hypertonic vehicle might hasten absorption.
For Intracutaneous
Injections: Intracutaneous route is used for diagnostic purposes. And the
diagnosis is dependent on the subsequent development of an immune response
involving inflammation. Thus diagnostic preparation should be isotonic since a
paratonic solution might cause a false reaction.
For Intrathecal
Injections: These must be isotonic. The volume of C.S.F is only 60-80ml. Hence
a small paratonic solution will disturb the osmotic pressure and may cause
vomiting and other effects.
Example:
Compound
Concentration range
(%)
Mannitol
0.4 – 2.5
Dextrose
3.75 – 5.0
NaCl
Varies
Na-sulfate
1.1
Sorbitol
2.0
Stabilizer:
To maintain the
require stability, parenteral preparation must fulfill the following
requirements: --------
Adjust of PH:
Adjustment of PH is a major method of stabilizing injection because
decomposition is often catalyzed by hydrogen (H+) or hydroxyl (OH-
Addition of reducing
agents or antioxidants: Addition of reducing agents or antioxidants prevents the
oxidation of the products by the following ways:
By being
preferentially oxidized and thereby gradually used up.
By blocking an
oxidative chain reaction in which they are not usually consumed.
In addition, certain
compound known as effectiveness of antioxidants, particularly those blocking
oxidative reaction. On the other hand some chelating agents are used in this
connection in that they complex with catalysts that otherwise would accelerate
the oxidative reaction.
There are four types of antioxidants:
Example:
Compound
Concentration range
(%)
Antioxidants (reducing agents)
Ascorbic acid
0.02 – 0.1
Na – bisulfite
0.1 – 0.15
Na – metasulfite
0.1 – 0.15
Antioxidants
(blocking agents)
Ascorbic acid esters
0.01 – 0.015
BHT
0.005 – 0.02
Tocopherols
0.05 – 0.075
Synergists
Ascorbic acid
0.01 – 0.05
Citric acid
0.005 – 0.01
Tartaric acid
0.01 – 0.02
Chelating agents
EDTA salts
0.01 – 0.075
Replacements of air
by an inert gas: Presence of oxygen is a serious cause of decomposition. Thus
to improve stability, oxygen must be replaced by an inert gas from the final
container. Eg. Influx of N2 in ergot alkaloid containing injection.
Use of sequestering
agents: Trace qualities of many heavy metal ions often catalyze destructive
changes in medicaments. Such as Cu, Pb, Hg and Zn break the S-containing ring
of penicillin-G. Cu, Fe and Cr cause oxidation of adrenaline. These effects can
often be prevented by adding a substance called sequestering agents that will
form a water soluble co-ordination compound with metal and cease
ionization.
Example:
Ethylenediaminetetra
acetic acid (EDTA)
Dimercaprol
Na-polymetaphosphate
Preservatives:
Preservatives or
antibacterial agents must be present in multi-dose containers. They must be
added in adequate quantities to prevent the multiplication of micro-organism
which may be accidentally introduces into the preparation while withdrawing a
dose from the multi-dose containers.
The desirable
features of a suitable preservative for multi-dose injections were summarized
as: ------
Should be able to
prevent the growth of and preferably to kill contaminating organisms.
Should be compatible
with the medicament, even on long storage.
Should not interfere
with the therapeutic efficacy of the product.
Should have low
absorption rate into rubber.
Should be non toxic
to the patient.
Should have a broad
spectrum of activity to include fungi as well as vegetative bacteria.
Should be active over
a wide PH range.
Should be
uninfluenced by the container.
Should be stable in
aqueous solution at high temperatures if the injection is to be sterilized by
moist heat process.
Limitations:
Bactericidal agents cannot be used in Infusion fluids. Also it should not be
used in Intra-cardiac, Intra-arterial, Intrathecal, Intracisternal and
Peridural Injections.
Eg.
Compound
Concentration range
(%)
Benzyl alcohol
0.5 – 10.0
Butylparaben
0.015
Metacresol
0.1 – 0.25
Methylparaben
0.01 – 0.18
Phenol
0.065 – 0.5
Phenylmercuric
nitrate
0.001
Propylparaben
0.005 – 0.035
VEHICLE:
For the preparation
of parenteral products one will have to use a suitable vehicle for dissolving
or suspending the medicaments. The vehicle used for the parenteral preparations
must have the following criteria: --------
Should be
pharmacologically inert.
Should be pure and
non-toxic (compatible with blood, non-sensitizing and non-irritating.).
Should maintain the
solubility of the drug.
Should be chemically
and physically stable.
Should be unaffected
by PH change.
Should not interfere
with the therapeutic activity of the medicaments.
Vehicles used for
parenteral preparation can be divided into two main types: --------
Aqueous
Non – aqueous
Aqueous solvents: The
vehicle used in parenteral products has the first preference for the aqueous
solvents i.e. water because:--
Aqueous preparations
are tolerated well by the body.
They are safest and
easier to administer.
It is more available
and cheapest.
The following aqueous
vehicles are used for the preparations of parenteral products: -----
Water for Injections
U.S.P:
This water is purified
by distillation or by reverse osmosis or diamination.
It is well tolerated
by the body and ionizable electrolytes readily dissolve in water.
It is not required to
be sterile but must be pyrogens free.
It must also have a
high level of chemical purity.
It meets the total
solid content of not more than 1mg/100ml and may not contain added substances.
It should be freshly
boiled, cooled and stored in a well closed container to avoid reabsorption of
O2 and CO2.
It should be stored
in tight container at temperature below and above the range in which microbial
growth occurs.
It is intended to be
used within 24 hours following its collections.
Sterile Water for
Injections U.S.P:
This water has been
sterilized and packaged in single-dose containers of not more than 1 liter
size.
It must be pyrogens
free and may not contain anti-microbial agents.
It may contain a
slightly greater amount of solid than water for Injections.
It is intended to be
used as a solvent, vehicle or diluents for already sterilized and packaged
injectable medication.
Bacteriostatic Water
for Injections U.S.P:
This water is
sterilized water for injection containing one or more suitable anti-microbial agents.
It is packaged in
vials containing not more than 30ml of the water.
The container label
must state the name and proportion of the anti-microbial agent present.
It is employed as a
sterile vehicle in the preparation of small volumes of injectables
preparations. (Because large amount of anti-microbial agent is harmful for the
body.)
Sodium Chloride
(NaCl) Injections U.S.P:
It is sterile and
isotonic solution of NaCl in water for injections.
It contains no
anti-microbial agent and the content of Na+ and Cl- ion is about
154 mEq of each per
liter.
It is used as a
sterile vehicle in preparing solutions or suspensions of drugs for parenteral
administration.
Bacteriostatic Sodium
Chloride (NaCl) Injections U.S.P:
It is sterile and
isotonic solution of NaCl in water for injections.
It contains one or
more anti-microbial agent which must be specified on the labeling.
It may not be
packaged in containers greater than 30ml in size.
Ringer’s Injections
U.S.P:
It is a sterile
solution of NaCl, KCl and CaCl in water for injections.
These agents are
present in concentrations similar to physiological fluid.
It is employed as a
vehicle for other drugs, of alone as an electrolyte replenisher and fluid
extender.
Non – Aqueous
solvents: Oily vehicles are used when the use of water in contraindicated in
one way or the other eg. -------
When the medicament
is insoluble or slightly soluble in water.
To increase the
stability of the preparation.
To prolong the
duration of action of a drug.
Criteria of
non-aqueous vehicles:
Should be nontoxic,
non-irritating and non-sensitizing.
Must not adversely
affect the active ingredients.
Should not exert
pharmacologic activity of its own.
Must be administered
intramuscularly.
The physical and
chemical properties of the solvents would be suitable for the task at hand
before they are employed.
Must maintain its
fluidity over a wide temperature range.
Should have high
boiling point to permit heat sterilization.
Should have proper
miscibility with body fluids and lower vapour pressure to avoid problems during
heat sterilization.
Disadvantages of
non-aqueous vehicles:
They may be too
viscous in cold weather to administer without warming.
They often cause pain
at the site of the injections.
They will contaminate
the syringe and needle making them difficult to clean.
They must be used
only by the intramuscular route, since their accidental intravenous injection
may lead to thrombosis.
Types of non-aqueous
vehicles: The following non-aqueous vehicles are used for the preparation of
parenteral products:
Water miscible
vehicles: Dioxalanes, Dimethyl acetamide, Polyethylene glycol, Propylene
glycol, Glycerin and ethanol etc.
Water immiscible
vehicles: Fixed oils (vegetable origin) eg. Corn oil, Cottonseed oil, Peanut
oil, Olive oil, Sesame oil, ethyl oleate, isopropyl myristate and
Dimethylacetamide etc.
WATER FOR INJECTIONS
U.S.P:
Water for injections
is the most extensively used vehicle in parenteral preparations. This water is
purified by distillation or by reverse osmosis or diamination process. It
occurs as a clear, colorless and odorless liquid. It has the following specific
criteria than other liquids or waters: ------
It is well tolerated
by the body and ionizable electrolytes readily dissolve in water.
It is not required to
be sterile but must be pyrogens free with less than 0.25 endotoxin units per
ml.
It must also have a
high level of chemical purity.
It meets the total
solid content of not more than 1mg/100ml and may not contain added substances.
It should be freshly
boiled, cooled and stored in a well closed container to avoid reabsorption of
O2 and CO2.
It should be stored
in tight container at temperature below 40C and above 370C, the range in which
microbial growth occurs.
It is intended to be
used within 24 hours following its collections.
Preparation of water
for injections:
Apparatus: The usual
method of preparing water for injections is distillation. In distillation
process, metal still is suitable for preparing water for injections. In
general, the conventional still is composed of:
A boiler or
evaporator containing feed water or distilland.
A heater (source of
heat to vaporize the water.)
A headspace with
condensing surface known as baffles (for returning non-volatile impurities to
the distilland or water.)
A condenser (removes
the heat of vaporization and converts the water vapour to a liquid.)
Procedures: The
following procedure is followed for the preparation of water for
injections:----
The source of water
used in the preparation of water for injections by distillation may be
contaminated with suspended mineral & organic substances, mineral salts and
chemicals. Thus to improve the quality of the end product the source water may
be pretreated by: ----
Chemical softening
Filtration
Deionization
PH adjustment
Carbon adsorption
Then the feed water
is heated in the evaporator for boiling.
The vapor produced in
the tubes is separated from the entrained distilland in the separator and
conveyed to a compressor.
Within compressor,
the vapor is compressed and raised its temperature to approx. 1070C.
It then flows to the
steam chest where it condensed on the outer surfaces of the tubes containing
the distilland.
The vapor is thus
condensed and drawn off as a distillate.
Collections and
tests: In operation, the first portion of the distillate must be discarded. The
remainder is collected in a suitable storage vessel. The chemically quality of
the freshly collected distillate should comply with the limit tests for
purified water. However, it will typically have the following additional
quality limits:
Chlorides
Less than 0.5 p.p.m.
Ammonia
0.1 p.p.m.
Heavy metals
0.1 p.p.m.
Oxidizable substances
Less than 5 p.p.m.
Residues on
evaporation
Less than 0.001%
PH
5.0 – 7.0
Storage: Care is
required in handling the freshly collected distillate as it is subject to
microbial contamination during storage and distribution. Two systems are
commonly used for the storage of water for injections: -------
Batch storage
Dynamic storage
CONTAINERS:
Container is a vital
factor for the preparation especially of parenteral products because, these are
in intimate contact with the product, the desirable properties for containers
of injections is as follows: -----
The containers should
maintain the sterility of the packed fluids and also be compatible with the
packed fluids.
There should be no
surface changes of the container at the temperature and pressures associated
with sterilization.
They should protect
photosensitive contents from the light.
In hospital practice,
for economic reasons, it should either be cheap enough to dispose of after one
use or be easy to clean and reuse.
The contents should
be easy to examine through the containers to detect particles, contamination
and decomposition.
They must be non
reactive, non toxic and not to impart to the product taster or odors.
They must be
adaptable to commonly employed high-speed packaging equipment.
Generally the
following two types of materials are used to prepare containers for packaging
the parenteral preparation: ------
Plastic
containers
Glass containers
Plastic containers:
Plastics are
synthetic polymers of high molecular weight. Plastics are in regular use for
packaging certain types of sterile products including infusion and dialysis
fluids.
General properties:
They are sensitive to
heat and may melt or soften at below 1000C.
They are light in
weight. So easier to handle and cheaper to transport.
Mechanically they are
almost as strong as metals.
They are poor
conductors of heat.
Generally they are
resistant to inorganic chemicals but often attacked by organic substances.
(solvents and oils)
Very few types
completely prevent the entry of water vapour at all the temperature to which an
injections containers may be exposed.
Advantages:
They are cheap
materials and easy to mould.
They are flexible and
not easily broken.
They are of low
density and thus light in weight.
They can be heat
sealed.
They are suitable for
use as containers, closures and as secondary packaging.
Disadvantages:
They are not as
chemically inert as glass.
Some plastics are
very heat sensitive.
Some plastics undergo
stress cracking and distortion on contacting some chemicals.
They are not as
impermeable to gas and vapour as glass.
They may possess an
electrostatic charge which will attract particles.
Additives in the
plastic are easily leached into the product.
Generally the plastic
used to pack injections are thermoplastic in nature. These soften on heating to
a viscous fluid and harden on cooling. Those uses include: -------
Polyethylene
(polythene)
High-density
polythene
Polyvinyl chloride
(P.V.C)
Polystyrene
Polypropylene
Polytetrafluoroethylene
(Teflon)
Polyamides (nylon)
Polycarbonate
Polyethylene
(polythene):
Advantages:
It is flexible, very
light but tough plastic that is practically impermeable to water vapour.
Pure polythene frees
from plasticizers and others adjuncts.
It is non toxic to
human tissues even when implanted for long periods.
Disadvantages:
It has relatively
high permeability to gases cause drug deterioration. (Penetration of O2 can
lead to discoloration of tetracycline suspensions).
Certain oils and
preservatives may penetrate through it.
It has lack of
transparency.
It tends to charged
with static electricity which attracts dust.
Sterilization is
difficult because its melting point range is 1100C – 1150C and begins to soften
at about 900C.
Uses: It is widely
used for bottles, tubing and heat sealable packaging films due to its water
impermeability and ease of fabrications.
High – density
polythene:
Advantages:
It is more rigid and
consequently handling and filling of containers is easier and their walls can
be thinner.
Its permeability to
gas is low and resistance to oils high.
It can be sterilized
by autoclaving due to its higher melting point.
Uses: It is used for
disposable syringes and the packaging of infusion fluids.
Polyvinyl chloride
(P.V.C):
Advantages:
It has high clarity.
It is practically
unaffected by sunlight.
Its un-plasticized
materials are non toxic.
It is less permeable
to gases than polythene.
Its plasticized
grades are good oil resistant.
Some grades can be
sterilized by autoclaving.
The surface can be
printed readily.
Disadvantages:
It is less flexible,
heavier and much more permeable to water vapour.
It adsorbs some
drugs.
It require an
extended sterilization time due to its heat resistance.
For most heat
sterilization requires air ballasting to avoid pouch explosion.
Uses: P.V.C
collapsible bags are used to package most infusion fluids.
Polystyrene:
Advantages:
It is light &
cheap materials and easy to mould.
It is odorless,
tasteless and available in transparent.
It has excellent
dimensional stability that assure to fine limits of accuracy.
It softens at a lower
temperature than other plastics.
Disadvantages:
It is hard and rigid
materials.
It is brittle to
cold.
It permits the
permeability of water vapour than others plastics.
It tends to be
electrostatic and very permeable to aromatics flavourings.
Polypropylene:
Advantages:
It is the lightest
known plastics.
It has greater heat
resistance.
It has very high
resistance to repeated flexing.
It can be autoclaved
repeatedly.
Uses: It is used for
disposable syringes. It is the best plastic to date for dialysis fluids and
irrigations.
Polytetrafluoroethylene
(Teflon):
Advantages:
It has excellent heat
resistance.
It resists all known
solvents and chemicals except gaseous fluorine.
Its water absorptions
are nil.
Its moisture vapour
permeability is less than that of polythene.
Disadvantages:
It is very expensive
and difficult to fabricate.
Polyamide:
Advantages:
It has excellent heat
resistance.
It has good
resistance to vegetable oils and many solvents and chemicals.
It can be autoclaved
repeatedly at 1210C.
Disadvantages:
It is not
transparent.
Its water vapour
permeability is relatively high.
Polycarbonate:
Advantages:
It has excellent
dimensional stability.
It is transparent.
It has very good heat
resistance.
Its water absorption
is low.
It is not susceptible
to oxidative degradation.
Glass containers:
Glass is the first
preferred materials of container for parenteral products. Glass is composed
principally of the silicon-dioxide (SiO2) tetrahedron. It is physico-chemically
modified by the treatment with such oxides as those of Na, K, Ca, Mg, Al, B and
Fe.
The most chemically
resistance glass is composed almost entirely of sodium dioxide (Na2O2) but it
is relatively brittle and can only be melted and molded at high temperature.
Boric oxide somewhat modified the above characteristics.
Advantages:
Glasses are
transparent and chemically inert.
They are impervious
to air and moisture.
They are easy to
clean and sterilized by heat.
They are strong.
They may be used for
products which are incompatible with plastic containers.
Disadvantages:
They are much heavier
than plastic and less transportable.
They are brittle and
subject to damage during transport and storage.
During use they
require the use of an air inlet filter device for pressure equilibration within
the container.
Particles of glass
can be released into the injection fluids.
They are unsuitable
for moist heat sterilization.
They are fragile and
expensive than plastic.
On the basis of the
results from the official test, glass compounds are classified into four types:
--------
Types I glass
Types II glass
Types III glass
NP glass
Types I glass
(Borosilicate glass):
Compositions:
This is a borosilicate
glass or pyrex glass. It is principally composed of silicon-dioxide (SiO
2) and boric oxide
with low level of the non-network forming oxides. The approximate composition
of the pyrex glass are as follows: --------
80% SiO2
2% Al2O3
12% B2O3
6% Na2O + CaO + other
oxides
Characteristics:
It is a chemically
resistant glass (lowest leachability).
It has a low thermal
co-efficient of expansion.
It is difficult to
melt and mold.
Uses: Borosilicate
glasses are used for chemical glassware, ovenware and containers for alkali
sensitive preparation. Now a day, in our country, it is not widely used for
injection containers although some antibiotic vials are made from it.
Types II glass
(Treated soda-lime glass):
Compositions:
It is treated soda-lime
glass. It is treated under controlled temperature (above 5000C) and humidity
conditions with SO2 to dealkalize the surface of the container by producing a
Na-sulfate (Na2SO4) layer. This process is known as “Sulphuring”. This surface
is chemically more resistant but repeated sterilization and alkaline detergents
will breakdown this dealkalized surface.
Characteristics:
It is chemically less
resistant and melts at a lower temperature.
It is easier to mold
into various shapes.
It has a higher
thermal co-efficient of expansion than type I.
Types II glass
usually has a lower concentration of the migratory oxides than types III.
Uses: It is used for
the containers of blood, Plasma and infusion fluids. It is also used for a
solution which is buffered has a PH below 7 or is not reactive with the glass.
Now a day, it is used in our country for dry salt penicillin vials.
Types III glass
(Regular soda-lime glass):
Compositions:
It is regular
soda-lime glass. It contains approximately: -------
75% SiO2
10% CaO
15% Na2O
<1% Al2O3, MgO,
K2O
The Al2O3 improves
mechanical strength and chemical durability and makes melting easier. MgO
reduces the manufacturing temperature of glass and widens the temperature range
over which the glass can be shaped into containers.
Characteristics:
It is sufficiently
resistant to the action of water for ordinary purpose.
It is unsuitable as a
container materials for many injections because: ------
It yields an
appreciable quantity of alkali to water.
Flakes separate
comparatively easily.
On repeated use its
surface loses some of its brilliance.
It’s relatively high
co-efficient of expansion makes it liable to fracture with sudden changes of
temperature.
Uses: It is used
principally for anhydrous liquids or dry substances.
NP glass (Non
parenteral glass):
This is a soda-lime
glass (general glass) and composed of sodium oxide (Na2O) and calcium oxide
(CaO). They are not suitable for parenteral solutions containers because it
provide the least chemical resistance. So it is used for non-parenteral
products such as tablets, capsules, oral solutions and suspensions etc.
CLOSURES:
Rubber consists of
long chain polymers of isoprene units linked together in the cis-position.
Hevea braziliensis is the most important source of rubber. Its latex contains
30% to 40% of rubber in colloidal suspension. Usually closures for parenteral
products are made from -------
Natural rubber
Synthetic rubber
Characteristics of
good pharmaceutical rubber: A good pharmaceutically used rubber consists the
following criteria:
Should show good
ageing property.
Should have
satisfactory hardness and elasticity.
Should have
resistance to sterilization conditions.
Should not affect by
moisture and air.
Should have low
permeability to moisture and air.
Should have
negligible release of undesirable substances.
Should have
negligible extraction of injection ingredients.
Natural rubber:
Disadvantages: The
chief disadvantages of raw rubber are: -----------
Its elasticity is
poor.
Its strength is poor.
It’s hardens when
cold and become soft and sticky when warm.
It dissolves in many
solvents.
Thus a large number
of substances are added to give better chemical and physical properties and
facilitate manufacture. Such as: ------- ---------
A Vulcanizing agent:
It improves its strength and reduces its susceptibility to temperature changes.
Example: Sulpher.
Accelerators: It
improves its strength and resistance to oxidation. Example: Thiazoles (2
mercaptobenzthiazole), Thiurams (tetramethyl thiuram disulphide).
Activators: It
increases the activity of accelerators. Example: Stearic acid or Zinc stearate
for M.B.T. and Zinc oxide for T.M.T.
Softeners: It
influences the hardness of the finished products. Example: Pine oil, Mineral
oil.
Fillers: Rein forcing
fillers improves physical properties and extending fillers used as diluents to
reduce its cost and partly to facilitate manufacture. Example: Carbon black,
Talc, Whiting, Asbestos.
Antioxidants: It
protects the oxidation of rubber. Example: Phenyl betanapthylamine and
Para-hydroxydiphenyl.
Special ingredients:
Paraffin wax produces a protective barrier to oxygen attack and water
absorption. Resin increase tackiness.
Synthetic rubber:
Characteristics: In
general they are: ----------
More resistant to
high and less resistant to low temperatures.
More resistant to the
agents that accelerate ageing e.g. Light, Oxidation & its catalyst, Copper
and Manganese.
More difficult to
process.
More expensive.
Types: The following
four types of synthetic rubber are used as closure materials for parenteral
products: -
Butyl rubber: These
are co-polymers of isobutylene with 1% to 3% of isoprene or butadiene.
Nitrile rubber: These
are butadiene-acrylonitrile co-polymers. It is highly oil resistances.
Chloroprene rubber:
These are polymers of 1:4 chloroprenes. It is polar and highly resistant to
oil. It is also resistance to oxidation.
Silicon rubber: They
are made by polymerization of methyl silicon fluids. Nitrile groups are
sometimes introduced to improve oil resistance.
DIFFERENCE BETWEEN
SINGLE-DOSE AND MULTI-DOSE CONTAINERS
Single-dose container
Multi-dose container
A single-dose
container is a hermetically sealed container.
A multi-dose
container is sealed in such a way that the rubber closures allow the withdrawl
of doses by puncture with hypodermic needles.
It contains only one
dose of the sterile drug.
It contains a number
of doses of sterile drug.
The container is once
opened it cannot be resealed with assurance that sterility has been maintained.
Because of using the
rubber closures, successive portions of the contents can be withdrawn without
changing the strength, quality or purity of the remaining portion.
Commonly single-dose
injections are known as ampoules which are sealed by fusion of glass of the
container under aseptic conditions.
Commonly multi-dose
injections are known as vial which is a small glass container with non
removable rubber top through which a needle is inserted to withdraw the
solution.
The volume is very
small.
The volume should
normally not exceed 30ml for vial.
In single-dose
injection presence of preservatives must not necessary.
Preservative is
necessary in multi-dose injections.
In single-dose
container there is no used in closures.
The closures used in
multi-dose containers create many problems which must be taken care of before
selecting the closure. The problems are: -----
Absorption of
materials from the products.
Shedding of
undesirable soluble or insoluble components to the preparation.
Sometimes the closures
react with the products.
Here glass containers
are usually used
Here both glass and
plastic containers are used.
These types of
containers are breakable.
These types of
containers are unbreakable, light and disposable.
Accurate dose
measurement is done in single-dose containers.
Wrong dose measurement is done in multi-dose
containers.
DESCRIPTION:
HEPA (High efficiency
particulate air) filters are composed of ----------------
Various fibers like
glass fiber, ceramic materials.
A continuous sheet of
filtration materials.
Pleated fiberglass
paper as the filter medium.
The parallel pleats
of this filter material increase the surface area of the filter and also
increase the air flow through the filter. Within the structure of the filter,
the filter material is sealed to an aluminium frame. At least one side of the
filter is protected with a coated mild steel mesh. Efficient gaskets are used
to ensure that air cannot leak part the filter material or past the filter unit
when it is mounted in its trunking. HEPA filters exhibit:
A high flow rate.
High particulate
holding capacity.
Low pressure drop
across the filter.
MECHANISM OF ACTION:
For clean room, air
exits from the filter face at a rate of about 0.45 m/s and have 99.997%
efficiency at removing 0.3(m particles. The initial pressure difference across
the depth of the filter is about 130 Pascal (Pa) and at the end the pressure
will increase to about 490 Pa.
Larger particles by
inertial impaction.
Medium-sized
particles by direct interception.
Small particles by
Brownian diffusion.
The efficiency of
removing particles is affected by the air velocity and the filter packing.
Larger and smaller particles will be removed more efficiently.
EFFICIENCY:
HEPA filters are
capable of removing 99.99% of particles down to 1(m at an average air velocity
of 100 ft/min (0.54 m/sec). The US
Quality control:
Quality control is a
part of quality assurance. Quality control refers to the process of striving to
produce a perfect product by a series of measures requiring an organized effort
by the entire company to prevent or eliminate errors at every stage in
production. It concerns quality control of raw materials, finished products and
packaging materials.
In the preparation of
parenteral products strict quality control test must be carried out throughout
the entire process of the preparation of parenteral products to give ensure
that the final product must meet the specific standards. For this purpose, raw
materials must be subjected to quality and pyrogens test. Various test and
assay must be carried out for finished products to ensure that they must meet
the required specification. In addition to the usual chemical or biological
test, the following test must be carried out on the finished products of
parenteral preparations for their standardization: --------------
Sterility test
Clarity test
pyrogen test
Leaker test
Sterility test:
These tests are
performed on all lots of injections in their final containers. Hence samples
may be taken at random to represent the entire lot of the preparation.
According to the U.S.P. there are two basic method for sterility testing:
-----------
Direct inoculation of
test sample on culture media
Filtration technique.
Direct inoculation
method:
In this method, an
aliquot quantity of test samples are transferred into culture tubes containing
Fluid Thioglucolate Medium (FTM) or Soybean-Casein Digest Medium (SCDM). Then
the tubes plugged with sterilized cotton wool and incubated at 20-250C
temperature for 7 to 14 days for SCDM or 30-350C temperature for 7 to 14 days
for FTM.
At the same time,
positive and negative control test are carried out under the same condition to
confirm the sterility and growth promoting activities of the medium. The whole
operation must be carried out under aseptic condition to prevent the accidental
entry of microorganism into the test.
Results: If here is
no growth of microorganism appears in the tubes, the test materials are
considered to be sterile. But, there is any growth; the test must be repeated
for 2nd time with fresh test sample and culture media because in the first
time, the microbial growth may be due to accidental entry of microorganism. If
the 2nd time also shows the growth it may be repeated 3rd time very carefully.
If this time also growth appears, then the materials fail to pass the sterility
test.
Filtration method:
In this method, the
testing solution passed through the membrane filter having sufficiently small
pore size to retain bacteria. Then the membrane is washed by isotonic salt
solution to remove at least inhibitory properties. Then one half of the filter
is transferred asceptically to appropriate culture media and incubated at
20-250C temperature for 7 days for SCDM and 30-350C temperature for 7 days for
FTM.
At the same time,
positive and negative control test are carried out under the same condition to
confirm the sterility and growth promoting activities of the medium. The whole
operation must be carried out under aseptic condition to prevent the accidental
entry of microorganism into the test.
Results: If here is
no growth of microorganism appears in the tubes, the test materials are
considered to be sterile. But, there is any growth; the test must be repeated
for 2nd time with fresh test sample and culture media because in the first
time, the microbial growth may be due to accidental entry of microorganism. If
the 2nd time also shows the growth it may be repeated 3rd time very carefully.
If this time also growth appears, then the materials fail to pass the sterility
test.
If the product has
antimicrobial activity, they must be neutralized or eliminated by dilution. For
solids or oily materials which make the culture medium turbid and make it difficult
to conclude, whether the turbidity is due to microbial growth or due to
materials itself, the normal test may have to be modified by sub-culturing the
medium. If turbidity in sub-culture does not appear the materials is sterile
but if turbidity appears due to microbial growth which shows that the material
is not sterile.
Pyrogen test:
Pyrogen: Pyrogens are
the metabolic products of microorganism that are produced by all microorganism
like Gram positive (+ve), Gram negative (-ve) bacteria and fungi. They are
soluble, filterable, thermostable and non volatile substances polysaccharides
or an amino acid carrier. When introduced in human beings they caused febrile
reaction which includes: ------------
Chillis and fever
with headache.
Pain in the back and
legs.
At high dose levels
it will also: -----------
Activated the
coagulation system.
Alter carbohydrate
and lipid metabolism.
Produce platelet
aggregation.
Produce shock and
ultimately death.
According to B.P.
there are two types of test are available for pyrogen testing include:
---------------
Rabbit test
LAL test
Rabbit test:
Only healthy and
mature rabbit should be used because they show similar physiological response
to pyrogenic substances like that of man, but they are very sensitive to
external stimuli. A suitable quantity of test samples (10ml/kg) is administered
into the ear vein of the rabbit. Rectal temperatures are noted at 1, 2 and 3
hours after the introduction of the injection.
Results: If no rabbit
shows the individual temperature rise in 0.60C or more above and if the sum of
the three individual maximum temperature rise does not exceed 1.40C, the test
sample meets the requirements for the absence of pyrogen.
If any rabbits show
the individual temperature rise in 0.60C or more above and if the sum of the
three individual maximum temperature rise exceeds 1.40C repeat the test using
five another rabbits. If not more than 3 out of 8 rabbits show individual
temperature rise in 0.60C or more and if the sum of the 8 individual maximum
temperature rise does not exceeds 3.70C the test sample meets the requirements
for the absence of pyrogen.
LAL test:
This test commonly
referred to as the limulus amoebocyte lysate (LAL) test. It is an in vitro test
for bacterial endotoxin or pyrogens use a lysate of amoebocyte from the
horseshoe crab Limulus polyphemus.
Procedures: In the
test procedure, the lysate is mixed with an equal volume of test solution on a
depyrogenate container. Then the container is incubated undestrubly at 370C for
60 minutes, the end point is identified by gently inverting the glass tube.
At the same time,
positive and negative control test are performed under the same condition to
confirm the sterility and sensitivity of the lysate. The whole operation must
be carried out under asceptic condition to prevent the accidental entry of
microorganism into the test.
Results: A positive
result is indicated by the formation of a solid clot, which does not
disintegrate when the tube is inverted. A negative result is indicated if no
gel clot has been formed. This test will detect between 0.02 – 1.0 endotoxin
units/ml.
Advantages:
Advantages of LAL test are as follows: ------------
It is cheap
It is rapid
It is simple
It is sensitive to
low endotoxin concentrations.
Precaution: Before
the test is carried out it is necessary to determine that --------------
The test equipment
does not adsorb endotoxin
The lysate is of
suitable sensitivity
No interfering agents
are presents.
Leaker test:
Leaker lest is
performed to detect the presence of passage (capillary pores or tiny cracks)
for leaking of the content from the ampoule. In this test, unlabelled final
ampoules are dipped into deeply colored dye solution usually 1% methylene blue
(MB) solution. The whole process is carried out in a vacuum chamber under
negative pressure. When the vacuum is released the colored solution will enter
the ampoules through a defective sealing. After careful washing of ampoules
from outside, the dye solution can be seen in the leaker ampoules. And those
ampoules are rejected. Capillaries of about 15( in diameter can be detected by
this test method.
Disadvantages:
This test is not
performed on vials and bottles because of flexibility of rubber closures.
Moreover the dye will
badly stain the rubber stopper.
Clarity test:
Clarity test is
performed to detect the presence of particulate matter in parenteral
preparations. In this test, the unlabelled final containers are set up against
strongly illuminated white surface for the detection of light colored
particles. This test is done with naked eye. The containers are slowly inverted
and rotated. If any particular matter is visible, the package is rejected.
Sterilization:
Sterilization is the
process by which all viable microorganisms including spores are killed or
eliminated. OR The term “Sterilization” as applied to pharmaceutical preparations,
means the complete destruction of all living organisms and their spores or
their complete removal from the preparation. This is important in many fields,
particularly in surgery and in microbiological works.
Five general methods
are used for the sterilization of pharmaceutical products: -------------
Dry heat
sterilization
Moist heat
sterilization
Sterilization by
filtration
Gas sterilization
Sterilization by
ionizing radiation
Dry heat
sterilization:
Mechanism of action:
Dry heat treatments
have two targets: (1) Microorganisms & (2) Their by-products. The aim of
sterilization is to destroy the ability of microorganisms to survive and
multiply. Depyrogenation seeks to destroy the chemical activity of the
by-products, pyrogens or endotoxins (synonymous for the sake of simplicity).
Both processes
consist of an oxidation that is almost combustion. However the temperatures
required to achieve depyrogenation are distinctly higher than those needed to
obtain sterilization. Example: Fixed oil, Glycerin.
Advantages:
It can be used for
substances that would be harmed by moisture. Example: Oily materials and
Powders.
It is suitable for
assembled equipment, provided sufficient time for penetration is allowed.
Example: All glass syringes.
It is less damaging
to glass and metal equipment than moist heat.
Some articles of
porcelain can be sterilized by this method.
Disadvantages:
Most rubbers and
plastics cannot be sterilized by this method because they perish.
The drastic
conditions – high temperature, long exposure and very long heating up times
make this method to unsuitable for thermolabile products.
It is unsuitable for
surgical dressings.
It is a time
consuming process and needs high temperature.
Moist heat
sterilization:
Microorganisms can be
exposed to moist heat by using hot water, boiling water, steam at atmospheric
pressure (steaming) or steam under pressure (autoclaving). It can kill
microorganisms at lower temperatures and in shorter time than dry heat. For
example: All vegetative bacteria are destroyed at 1 hour at 800C and very few
will survive 10 minutes at this temperature. The spores of Clostridium tetani
are destroyed by 30 min. at 1150C.
Mechanism of action:
Moist heat is
believed to destroy microorganisms by causing protein coagulation or
denaturation. When heat is applied in the presence of sufficient water,
disulphide bonds and hydrogen bonds between the protein strands can be broken
and the strands have sufficient mobility to form new linkages resulting in the
denaturing of the protein, which if it is part of an enzyme will render it
inactive.
Advantages:
It is suitable for
surgical dressing.
Most medicaments,
rubbers and plastics are sterilized by this method.
It can kill microorganisms
at lower temperature and in shorter time.
PVC can be sterilized
by this method.
The apparatus is
inexpensive and simple.
Disadvantages:
It cannot be used for
substances that would be harmed by moisture. Example: Oily materials and
Powders.
It is more damaging
to glass and metal equipment than dry heat.
It cannot be used for
injections and articles, such as some plastics, that deteriorate at 1150C.
It is unsuitable for
assembled equipment, due to sufficient time for penetration is allowed. Example:
All glass syringes.
Sterilization by
Filtration:
Filtration through a
bacteria proof filter is a suitable method for sterilization of injections
containing thermolabile medicaments. Generally thermolabile medicaments would
suffer damage if subjected to heat sterilization. The process involves four
stages: --
Filtration of the
solution through a bacteria proof filter.
Aseptic distribution
of the filtered solution into previously sterilized containers.
Aseptic closure of
the containers.
Testing of sample for
sterility.
Mechanism of action:
The filtration
technique in sterilization flow the following mechanisms:
Straining: Here, the
pores of the filters are smaller than bacteria or other foreign particles. Thus
they easily retained when the solution are passed through the membrane filter.
Example: Remove of bacteria & fiber from parenteral products.
Retention on pore
irregularities: An organism passing along a pore in a sintered or fibrous
filter travels a tortuous path that has a very uneven surface. It has been
estimated that there are 2000 irregularities/cm of pore in an unglazed
porcelain candle. Bacteria may be stopped by or trapped in these hazards.
Impingement: As a
flowing fluid approaches a cylindrical object such as a fiber in the wave of a
filter cloth. Suspended solids may have sufficient momentum to strike the
fiber. If they do so they are retained but others may flow the steam lines and
be trapped a little later. An accumulation of solids builds up on the fibers
and eventually forms a cake over the surface.
Attractive force:
Here, electrostatic and other surface forces may exert sufficient hold on the
particles to attract and retained them.
Bridging and
entanglement: When using a fibrous filter cloth or filter pad the particles may
entangle with the fibers and form ridge over them. If there is insufficient
solid to form a cake then all particles must be removed by this mechanism.
There must be sufficient depth to the filter medium to ensure that they are
eventually trapped with a high degree of probability.
Advantages:
No heat is used, thus
ideal for thermolabile solutions.
Removes all bacteria
and fungi and often clarifies the solution.
Useful process for
sterilization of large volume solution.
Useful for eye drops
as dropper bottles do not withstand heating processes well.
Disadvantages:
Aseptic technique is
required. Thus highly trained staff and sterile equipment and facilities are
required.
Sterility tests are
required. Except in emergency, issue is not permitted until tests have been
passed.
Viruses, filterable
forms of bacteria and bacterial products such as toxins and pyrogens are not
removed or destroyed.
Filter may break down
either suddenly or gradually in use.
Filtration unit may
leak and permit entry of non sterile air.
Adsorption can occur
with some filters. Example: candles and fibrous pads.
Clogging can occur
with prolonged filtration.
Bacteria may grow
through some types of filters with lengthy filtration runs.
Filtration cannot be
used for sterilization suspensions.
Oxidation may occur
on larger filters and the medicament must be stable in the solvent.
Clean area:
Clean area is a room
with the environmental control of particulate and microbial contamination,
constructed and used in such a way as to reduce the introduction, generation
and retention of contaminants with the area.
Aseptic area:
Aseptic area is a
room or special area within the clean area designed constructed serviced and
used with the intension of preventing microbial contamination of the product.
Conventional flow:
Filtered air is
pumped into the room to produce a positive pressure compared to the exterior
and in a turbulent fashion of scavenge particles already present, flush them
out and so maintain clean condition.
Conventional air flow is defined in term of the no. of air change per hour.
According to B.P. standards ( 20 air change/hr.
Unidirectional air
flow:
Here the room is
conventionally swept by a cushion of filtered air. Laminar flow is defined in
terms of air velocity, parallel flow lines, may be either vertical or
horizontal. Complete laminar air flow has little practical application in
pharmaceutical product manufacturing.
Questions: How large
volume of parenteral solution must be isotonic in comparison to blood plasma?
Answer:
Large volume of
parenteral solutions must be isotonic in comparison to blood plasma. The
reasons can be understood from the following discussion: ------------------
The parenteral
solutions which have the same osmotic pressure of blood or 0.9% NaCl solution
is termed as isotonic preparations.
A solution with an
osmotic pressure greater than the blood plasma is called hypertonic solution
and a solution with an osmotic pressure smaller than the blood plasma is called
hypotonic solution. Now we can have an idea, actually what’s happened when
hypertonic or hypotonic solutions are administered in the blood – by observe
the following discussion: ---------------
Fragility shown by
blood cells:
When hypotonic
solution is given here the osmotic pressure, within the blood cell is larger
than the hypotonic solution. Therefore, solvent particle enters the blood cell
and make the cell bursts and irreversibly damage.
Crenulation shown by
blood cells:
When hypertonic
solution are given, the osmotic pressure outside the blood cell is larger,
therefore the liquid particles from the cell is extracted by the hypertonic
solution by osmosis and cause shrinkage. This process is called crenulation of
blood cell.
From the above
discussion we can easily conclude that, hypertonic or hypotonic solution may
hazard the red blood cell. Thus large volume of parenteral preparation must be
isotonic.
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