PARENTRALS

Dr. Shaimaa Nazar

 parentrals
• Any sterile solution suspension or
emulsion that is administered by
puncturing the protective barrier
of body i.e. skin and other outer
layer using an injection or
hypodermic needle .
 ADVANTAGES OF PARENTRAL
• Direct route of achieving drug effect in
the body
• Bypasses pre systemic or first pass
metabolism
• highest bioavailability among all
available dosage forms (nearly 100%)
• Drugs sensitive to gastric fluid can be
given
• Drugs which are unabsorbed orally
can be easily given
 DIS ADVANTAGES
• Production difficulties i.e. sterile condition is
require to be maintained through out the
processing cycle
• Administration requires a special skilled
personnel
• Puncture of skin is always essential so pain is
always associated during administration
 CLASSIFICATION OF PARENTRALS-
• Small volume parental: when volume is less
than 50 ml
• Large volume parental: volume is more than
100ml injection
They essentially need to be isotonic as may
cause haemolysis due to large volume.
 CHARACTERS OF PARENTRAL
• 1. Sterility
• 2. free of pyrogen
• 3. stability
• 4. freedom from particulate matter
• 5. isotonicity
 ROUTE OF ASMINISTRATION
• INTRA MUSCULAR ROUTE
It is second to IV in the quickness of onset of action.
1. the volume injected are 0.5-2 ml but can
extended up to 5ml.
2. normal onset of action is 15-30 minutes.
3. Major problem is vein damage and infusion in to
vein so aspiration before injection is advisable .
4. form a depot drug is slowly absorbed. The
absorption depends of particle size, type of
vehicle used, volume injected and isotonicity.
INTRAVENOUS
ROUTE

1. injected directly in to vein to achieve fastest

action.
2. provides maximum availability of drugs
3. drug effect is very difficult to terminate in case
of toxicity.
4. action is dependent of initial dose and biological
half life and kinetics of drug.
5. It is the only method of administration of large
volume parentrals also called as IV drips.
 SUBCUTANEOUS ROUTE
1. maximum volume 2ml.
2. probability of puncture of veins so aspiration is
needed.
3. Slower onset than IV or intramuscular.
4. Increased volume is injected called as hypo
dermolysis but irritation, pain and tissue
damage always accompanies.
5. Administration of hyaluronidase may help by
increasing absorption and decreasing tissue
damage.
6. Arm, leg and abdomen are the body portions
suitable for SC administration.
 PREFORMULATOON OF PARENTRAL
• Analytical property
• Molecular structure,
• assay of drug, impurities
• Phychochemical properties
• molecular weight,
• melting point,
• color
• odor ,
• solubility,
• particle size and shape,
• hygroscopicity,
• ionization constant,
• optical activity
• solvate formation polymorphism
• Stability and excipient compatibility
• Thermal stability,
• photo stability,
• effect of oxygen,
• resistance to sterilization,
• resistance to pH change
 FORMULATION ADDITIVES
• ANTI-OXIDANTS
• ANTIMICROBIAL AGENT
• BUFFERING AGENTS
• CHELATING AGENTS
• TONICITY ADJUSTING AGENTS
 ANTI-OXIDANTS
• molecule capable of slowing or preventing oxidation of
other molecules.
• Examples
• ascorbic acid and tocopherols
• synthetic antioxidants cystine, sulfates and propyl gallate ,
tertiary butylhydroquinone , butyrate hydroxyanisole
butylated hydroxytoluene etc.
• sulfates such as sodium bisulfite ,sodium metabisulfates
and sulfur dioxides are primly used in parental. Best suited
sulfates are shown to show allergic reactions in some
asthmatics so to avoid antioxidant deoxygination of vial
using an inert gas is preffered.
 ANTIMICROBIAL AGENT
• Substance kills or inhibits the
growth of microbes (bacteria,
fungi, protozoals or viruses).
• Any preservative system is necessary for
multiple dose vials.
• The preservatives used: meta cresol,
para hydroxy benzoate esters,
benzalkonium chloride,
chlorobutanol.phenol
 BUFFERING AGENTS
• Adjusts pH of solution
• The aim of adding buffer is maintain pH as
change in pH lead to product instability,
• solubility of drug dependent on pH.
• Buffer maintain maximum stability and
solubility.
• The factor aid change of pH of product are:
1. leaching from container, closure,
2. dissolved gases and chemical changes in any
of component
Here buffer capacity need to be studied before
selection of buffering agent .some buffering
•
CHELATING AGENTS
Chelation is binding or complexation of a bi- or
multi dentate ligand.
• Chelating agents form multiple bonds with single
metal ion. Presence of metal ion such as copper,
Zinc, iron catalyze the oxidative degradation.
• Sources of metal:
1. raw material impurities,
2. solvent, rubber stopper
3. container and equipment employed in product
manufacture.
chelating agents (EDDS) ,
Ethylenediaminetetraacetic acid (EDTA),
Oxalic acid ,Phosphoric acid , citric acid,
tartaric acid etc
 TONICITY ADJUSTING AGENTS
• dosage form must be isotonic or nearly
isotonic.
• Because as they are direct contact with
blood the difference in tonicity will
lead to exchange of ionic in
erythrocytes. This may cause hemolysis
if the volume given more than 100ml.
• agents added to aid tonicity are
dextrose, sodium chloride etc. .
• Antioxidants: Prevent oxidation :
Ascorbic acid
• Antimicrobial : maintain sterility
• buffers : maintain pH
• Buffering agents To achive buffering
capacity
• Tonicity modifiers: maintain
isotonicity with blood
• Chelating agents:chelate metallic
ions present
• Surfactants and To improve solubility
 PREPARATION OF FASCILITY
ENVIRONMENTRAL REQUIREMENT AND DESIGN OF
PRODUCTION AREA

• physical environment: refers to air born

particles and physical condition of air i.e.
temperature and moisture.
• Biological environment: water the purity and
microbial content of environmental air and
water.
 Production area
• The site chosen: provide
1. Adequate supply of raw materials.
2. transportation market proximity
3. energy availability ,
4. water quality,
5. air conditions and waste disposal facilities
Design of production area should have all the
quality to carry out production process smoothly.
 PRODUCTION AREA
• required conditions:
1. Sterility.
2. air conditioning.
3. humidity control .
4. whole area like wall, floor, ceiling, should smooth,
non- shedding and should easy to clean.
5. preparation and filling sterile condition is essential,
6. for filling lyophilized product humidity control is
essential .
7. For each process cleaning, drying ,air filtration,
sterilization cycle, and air control .
8. For visual inspection :production area should made
up of transparent glass. The air control, sterility
maintenance and cleaning system in production area
are the important factors.
 PERSONEL

• largest source of contamination

• performer as well as transmitter of
contamination.
• The main source of contamination is skin
flakes, scales, fragments of human hair,
droplets of air from breathing and coughing,
cosmetic, fabric etc.
• selection of personal for cleaning should
meet physical and mental condition
 STERILIZATION OF CONTAINERS

• is necessary before final product filled in to

the container.
• For sterilization of rubber components moist
heat sterilization is preferred as it penetrates
rapidly (slow penetrator like dry heat may dry
and crack rubber).
• Ethylene oxide also used.
 Glass containers
• Dry heat sterilization preferred.
• need to be pyrogen free .
• For plastic containers both steam sterilization and
ethylene oxide sterilization is used steam for high
density plastic and ethylene oxide for low density
plastic.
• Plastic also sterilized by ionizing radiation.
• NOTE- Siliconization done for rubbers and glass.
• silicone oil or aqueous emulsion of silicone is used .
for glass after application of silicone emulsion by
spraying in to vials it is dried at 250C for 5hrs that sticks
the silicone on the surface and kills pyrogen .
 Parentral formulations
• solutions, suspensions, emulsions or powders that
may be lyophilized or spray dried or simple
powder for reconstitution.
• The preferred one is aqueous solution.
• may also contain some co solvents like glycerin
and alcohol can be added.
• Solution are prepared by dissolving active
ingredient , excipient in solvent then maintaining
pH and tonicity by using suitable agents.
• The viscosity and surface tension of most of
product similar to water.
• The sterilization can be done by filtrations, or
autoclaving after filling and sealing .
• Multiple vial solutions should contain
antimicrobial agents.
 Suspensions
• active ingredient suspend in vehicle.
• suspension intended for parntral infusion:
viscosities of product as well as particle size
are prime factors.
• The formulation variable:
1. particle size.
2. particle size distribution.
3. zeta potential.
4. manufacturing variables. carefully
monitored.
• The requirement of suspension is
1. Syringibility: withdraw formula from container to syringe.
clogging, foaming tendencies and accuracy of dose measurement.
 Emulsions
• biphasic dosage form of oil phase and
aqueous phase where both phases are
liquid and immiscible and system is
thermodynamically instable.
• The emulsion must be:
1. physically and chemically stable,
2. progeny free,
3. sterilizable,
4. non antigenic,
5. Particle range 1-2 μm ,
6. stable to external temperature variations.
• Aqueous phase is water and oils used are
soybean oil, sesame oil, linseed oil, coconut
oil, olive oil etc.
as purity of oil is very important:
1. silicic acid treatment ,
2. winterization are done .
3. emulsification agents used (lecithin , spans
and tweens).
4. pH controlling buffers,
5. anti oxidants, and tonicity contributors are
contained in aqueous phase.
6. The neutrals agents such as glycerin and
propylene glycol are used
7. ionic agent like NaCl, KCl
1. emulsion contain drug in inner phase:
solubility and stability problems can be
minimized.
2. drug does not directly contact with the
external environment or body fluid so
partitioning of drug from internal phase to
external phase contribute to sustained release
of drug.
3. emulsion widely used for a patient requiring
long term parentrals nutrition.
4. Patients with deficiency of fatty acid, low
weight premature babies given parentrals fat
emulsion containing 10-20% of oil.
5. patients who cannot absorb through GIT are
caloriezed by using parentral fat emulsion.
• The emulsion is prepared by
1. mixing the two sterile phases of oil
and water , in which water phase
homogenized after mixing with
emulsifying agent and other agents
contributing to pH and tonicity .
2. the system then dispersed ,
homogenized and pH maintained
before filling.
 Dry powders
• used for
1. water sensitive drug.
2. drugs unstable in presence of
moisture.
The dry powders produced may
1. Lyophilize.
2. spray dried.
3. simple powders for re constitution.
• Lyophilization or spray drying : drying process
applied for pharmaceuticals which are thermo labile.
• Process of stabilization by removal of water:
1. rapid dehydration of powders.
2. sterile filling of powder minimizing chances of
contamination.
3. frozen mass is subjected to vacuum. The freezing
temperature should be below the eutectic point.
4. temperature increases but pressure decreases during
primary drying phase. The resultant is cake like mass.
secondary drying in which temperature increases and
vacuum decreases.
• In secondary drying removal of water takes place by
diffusion and desorption .
• After freeze drying product stoppered in that chamber
only as sealing outside may increase the risk of
contamination or variation of moisture content.
• Eutectic point: point at which intimate mixing
of ice and solute occurs such that they appear
as single phase. This point present only if solute
crystallizes when solvent is frozen.
• The requirement of powder for reconstitution is:
1. cleanliness,
2. sterility,
3. minimized moisture content,
4. uniformity,
5. good powder properties,
6. fast dissolving.
7. elegant appearance.
8. generally amorphous, or mixture of crystalline.
amorphous.
9. Expensive
10. requiring careful monitor of temperature, heat gain
or heat loss ,saturation moisture level of the
chamber as well drying rate.
 Sterilization methods
• Dry heat, gaseous and radiation
sterilization is generally preferred for
1. machineries.
2. Equipments.
3. container .
4. closures.
• Filtration sterilization is used to
sterilize vehicles, raw materials and
finished products which are heat
sensitive.
 Dry heat sterilization
• Dry heat sterilization sterilize glass .
• it is the only methode available to
make the machine and equipments
pyrogen free.
• has high penetration power and the
cycle of sterilization includes high
operating temperature and for long
periods.
• The cycle of sterilization is 260°C for
45 mins or 180°C for 120 min which
destroys pyrogen effectively.
•  
 STEAM STERILIZATION
• The medication in which packaging is
not sensitive to pressure can be
sterilized by this method.
• It involves temperature + steam
pressure for sterilization.
• autoclaves.
• The normal cycle include 20 min 15 lb
pressure for 121°C or 3 min 27 lb
pressure at 132°C.
 FILTRATION
• for heat sensitive products both liquids
and gases can be sterilized by this
process.
• membrane filters are widely used as
filter media. the filters may be made
up of plastic or sintered material .
• The pore of filter 0.2μm pored size is
generally preferred for sterilization
though smaller pore size also available
they significantly reduce the flow rate.
 FILLING OF PARENTRALS
• Important because it require accuracy
of fill volume, avoidance of
contamination during filing ie dust
pyrogen etc.
• during filling the maching should
maintain quality.
• parentrals generally filled slightely
more in volume so that the user can
take out the required volume from the
container.
1. For filling of suspension or powder vacuum pressure
displacement is used to have uniformity of content.
2. in vacuum displacement a gas is used to quantitize
the powder filled in to and the guns are under
vacuum to draw powder and adjusted to volume of
certain weight equivalent .
3. After filling the vial or ampoule is to be sealed.
4. Before sealing the oxygen in the container should
removed
5. inert gas like nitrogen or argon at an pressure of 2-3
psig before stopper insertion .
• design of tube depend up on
1. the mouth of ampule it is to be entered
2. viscosity and density of liquid to be
entered
3. flow pressure desired.
The tube should be freely pass through
mouth of the ampule to allow escape
of air during filling.
•