1) Parenteral products must be sterile, non-pyrogenic, and free of particulate matter as they are administered directly into the body. 2) Key factors in formulating parenterals include the vehicle, drug volume, adjusting isotonicity and pH, inclusion of stabilizers and preservatives, and ensuring the appropriate concentration and osmotic pressure. 3) Sterilization of parenterals can be achieved through various moist heat methods like autoclaving, dry heat like oven sterilization, or chemical methods using gases like ethylene oxide.

1. Parenterals
Formulation development
Pragati Kumar B
Asst. Proff.
Nimra College of Pharmacy
Vijayawada

2. Introduction and importance of the study
• Parenteral products are products that are administered
to the body by injection
• Because this route of administration bypasses the
normal body defense mechanisms, it is essential that
these products are prepared with a high degree of care
and skills than utilized in preparing conventional oral or
topical products.
• The finished product must be sterile, non-pyrogenic and
free from extraneous insoluble materials. These
products must satisfy a number of requirements for
parenteral products.

3. Sterile formulations must meet a
number of special criteria such as
• Sterility
• Particulate material
• Pyrogen free
• Stability
• pH
• Osmotic pressure

4. During the formulation of parenteral
products the following factors are critical
• The vehicle in which the drug is dissolved or
dispersed
• Volume (dose) of the injection
• Adjustment of isotonicity
• Adjustment of pH
• Stabilisers
• Preservatives
• Adjustment of specific gravity (for spinal
anaesthesia)
• Concentration units

5. Difference between parenterals
and other products
• Limits to the level of pyrogens present and of
particulate matter
• The injection route dictates the volume of
formulation. Hence the solubility of the drug
in the selected vehicle is critical in the
formulation

6. Vehicle
• The preferred vehicle is water as it is well tolerated
by the body, easy to administer and a large solvent
capacity
• Water for injection must be sterile and free from
pyrogens
• Cellulose, glass, rubber cores, cloth or cotton fibres
may constitute the contaminants list.
• Suitable filtration media for removal of particulate
material are sintered glass filters or membrane
filters with a pore size of 0.45-1.2 microns

7. Ph and Buffers
• As parenteral products are administered directly to tissues
and systemic circulation, formulations prepared should not
vary significantly from physiological pH, which is about 7.4.
• The acceptable pH range is 3-10.5 for i.v preparations and
4-9 for other routes.
• Buffers are included in injections to maintain the pH of the
packaged product.
• The buffers used in the injection must allow the body fluids
to change the product pH after injection.
• Acetate, citrate and phosphate buffers are commonly used
in parenteral products.

8. Osmotic pressure
• The osmotic pressure of the blood is approx.
300 milli Osmoles/L and ideally any sterile
solution would be formulated to have the
same osmolarity
• For eg: 0.9% w/v NaCl i.v solution has an
osmolarity of 308 milli Osmoles/L .
• 5% w/v Dextrose i.v solution has an osmolarity
of 280 milli Osmoles/L .
• NaCl, Mannitol or glucose can be used to
adjust osmolarity.

9. Antimicrobial agents
• Aqueous preparations which are prepared
using aseptic preparations and which cannot
be terminally sterilized may contain a suitable
antimicrobial preservative in an appropriate
concentration.
• Antimicrobial agents are added to multiple
dose vials to inhibit the growth of microbial
organisms which may occur accidentally and
contaminate the product during use.
• Antimicrobial agents must be effective in the
parenteral formulation

10. Antimicrobial preservatives
S.NO ANTIMICROBIAL AGENT CONCENTRATION (%w/v)
1 Benzalkonium chloride 0.01
2 Benzyl alcohol 1- 2
3 Chlorobutol 0.25 – 0.5
4 Phenol 0.5
5 Chlorocresol 0.1 – 0.3
6 Phenyl mercuric salts 0.002
7 Methyl hydroxy benzoate 0.1- 0.2

11. Atioxidants
• Aqueous solutions are more susceptible to
oxidation
• Bisulphites and metabisulphites are commonly
used antioxidants in aqueous injections.
• Injection formulations may in addition also
contain chelating agents, such as EDTA or citric
acid, to remove trace elements, which
catalyse oxidative degradation.

12. Sterilization
• Sterility :Absence of life or absolute freedom
from biological contamination.
• Sterilization : inactivation or elimination of all
viable organism and their spores.
• Disinfectant : substance used on non- living
objects to render them non- infectious; kills
vegetative bacteria, fungi, virus but not
spores. Eg: Formaldehyde
• Bactericide : ( Germicide) substance that kills
vegetative bacteria and spores

17. Advantages and disadvantages

19. Moist Heat
• Spore are killed by moist heat.
• Culture media & other liquids required
to retain their content of water.
• Not applicable to waterproof materials
such as oils and greases or dry
materials.

20. Pasteurization
• Moist heat at temperature below 1000 C.
• Heat labile fluids may be disinfected not
sterilized by heating at 560 C for 30 min.
• Sufficient to kill mesophilic bacteria but not
spores.
• For serum, or other body fluids containing
proteins, temp to rise above 59o C.
• UHT; 140o C less than 1 sec.
• Cold Pasteurization.
• High pressure pasteurization.

21. Washer Disinfectors
• Washing machines using hot
water, steam and detergents, may
be used.
• Washing action at 710 C for 3 min
or 800 C for 1 minute sufficient
to kill vegetative organism.
• Recommended for instruments
contaminated with HBV and HIV.
• Accordingly it is set at 93o C for
10 min.

22. Boiling at 100o C
• Heating in boiling water at 100o C for 5
minutes sufficient to kill all vegetative
bacteria, HBV and some bacterial spore.
• Used only in case of emergencies to sterilize
medical and surgical equipment.
• Heat labile articles and hollow or porous items
where water will not penetrate lumen cannot
be disinfected this way.

23. Steaming at 100o C
• To prevent glass from cracking which
happens when it is heated directly.
• Also in case of heat labile culture media.
• Pure steam in equilibrium with boiling
water at normal atmospheric pressure
• Exposure to this temperature for 5
minutes will kill microorganism.

24. Free Steaming
• Koch and Arnold steamers are used.
• Useful for selective heat labile media
like DCA, XLD, TCBS and Slenite F
broth.
• These media do not support the growth
of heat resistant bacteria.
• Tyndallization- 20 min for 3 succesive
days.

25. Steam sterilization
• Irreversibly coagulates and denatures
microbial enzymes and proteins.
• Important parameters for
effectiveness
1. Exposure time
2. Temperature of process
3. Level of moisture.
4. Pressure

26. 1) Advantages
• Non-toxic
• Cycle easy to control and monitor
• Inexpensive
• Rapidly microbiocidal
• Least affected by organic/inorganic soils
• Rapid cycle time
• Penetrates medical packing, device lumens
2) Disadvantages
• Deleterious for heat labile instruments
• Potential for burns

27. Autoclaves
• Invented by Charles
Chamberland in 1879.
• Precursor was the
Steam digester
invented by Denis
Papin in 1679.
• At correct temp lethal
to all
bacteria, viruses, fung
i & protozoa.

28. • Example of usage of autoclaves are:
• Hospitals & OPD- Porous load
autoclaves.
• Mortuary- Bench top autoclaves.
:
• Microbiology Lab: Media preparators or
fluid cycle steam sterilizers.
• Pharmaceutical- Fluid Cycle Sterilizer

29. Types of autoclaves
• Simple laboratory autoclave
• Transportable bench top autoclaves
• Large simple autoclave
• Downward displacement autoclave
• Multipurpose laboratory autoclave
• Pre vacuum
• High security autoclave.
• Porous load sterilizer.
• Low temperature steam.
• Steam flash pressure pulsing steam sterilization
autoclaves

31. • Sterilization Hold Time
• Heat Penetration Time
• Condensation of steam: 3 effects
1. Wets microorganisms.
2. Liberates latent heat.
3. Significant contraction of steam.

32. • Time and temperature with pressure required
for sterilization by steam under pressure in
autoclave.
• 121-124o c at 1.1 bar for 15 min.
• 134-138o c at 2.2 bar for 3 min.
1 bar=1 atm pressure=14.7 pounds
per square inch

33. • Steam which is present must be
1. Saturated:
2. Dry.
3. Pure.
 Steam supply:
1. Superheated steam ( Dry gas)
2. Wet steam

34. • Removal of air:
1. Simple transportable (pressure-cooker) autoclaves.
2. Downward displacement autoclaves.
3. Porous load autoclaves.
• Items to be put in autoclave
1. Unwrapped non porous items:
2. Porous loads
3. Discard loads
4. Fluids in sealed containers.
5. Nutrient media.

35. Simple laboratory autoclave
1. Considered unsatisfactory.
2. Not monitor temperature of load and
therefore cannot prevent spoiling
nutritive value.
3. No safety interlock.

36. Transportable bench top autoclaves.
• Sophisticated version of air displacement
autoclave.
• Possess automatic cycle control with
indicator for cycle failure and thermal
safety.
• Disadvantages of this are:
1. Not fitted with vacuum assisted air removal.
2. No assisted drying.
3. Cannot be used for porous loads, packaged
items or discard loads.
4. Cant handle liquid loads

37. Large simple autoclave
• Larger version of simple pressure
cooker.
• No means of assisted air removal.
• Size too large to permit removal of air.
• Unsuitable for wrapped articles and
make safe loads.

38. Downward displacement laboratory
autoclaves
• Provision for removal of air from chamber{
balanced pressure steam trap}
• Other devices assist the drying of the load.
• No vacuum assistance for air removal.
• Air removal was found to be inadequate.
• Only value is sterilization of unwrapped non-
porous metallic items.
• Cooling may take many hours to be below
80o C

39. Multipurpose laboratory autoclaves
• Different types of load require different cycles
required for these different loads.
Special feature
• Presence of efficient means of assisted air
removal and drying, assisted cooling and a
temperature sensitive probe reading directly
from the load.

40. Multipurpose laboratory autoclaves (
Contd)
• Aqueous media
1. Accelerated cooling required to avoid damage to
nutrient properties of culture medium.
2. Cooling to below 80o C before autoclave is opened
minimize risk of breakage and explosions.
3. Volume of DIN bottle which is used should be not
over 80%.
4. Duration of heating up period should be controlled
automatically with a thermocouple placed in one of
the largest bottle or simulators, which reproduces
thermal characteristic of bottle.

41. Multipurpose laboratory autoclaves (
Contd)
• 121o c for 15 min. Cooling of load should
be assisted so that media are cooled to
under 80o c in 30 min.
• Methods of cooling.
• Cooling time duration set by a
thermocouple placed in simulator
• Air blasting.
• Glasswares are satisfactorily processed
as part of a fluid cycle.

42. 1. High security autoclave
2. Porous load sterilizer
3. Low temperature steam

43. Gas sterilization
• For delicate heat labile equipments.
• Monitoring their efficacy by biological test.

44. 1. Low temperature steam
formaldehyde
• Steam at sub atmospheric pressure (temp
below 100o C) kills the spores of thermophilic
bacteria very slowly.
• Sporicidal at high concentration in presence of
moisture.
• Synergism between formaldehyde and steam.
• Difficulty in combining the two.

45. 2. Ethylene oxide sterilizer
• Useful also for small
proportion of medical
and surgical devices
which cannot withstand
autoclaving.
• Kills micro organisms by
altering their DNA by
alkylation
• only materials with
documented ethylene
oxide penetration and
dissipation properties
should be used as
wrappers.

46. Low temperature sterilization by ozone
• The 125 l ozone
sterilizer uses medical
grade oxygen water and
electricity to generate
ozone within the
sterilizer to provide
efficient sterilants
without producing toxic
chemicals or using high
temperatue.
• End of cycle O2 and
H2O are formed.

47. Liquid Sterilization
• To sterilize immersible devices like
endoscopes etc with 35% liquid
Peracetic acid.
• Done using STERIS system 1
• Acid is diluted with sterile filtered
water.
• Commercially available spores can be
used for monitoring sterilization.
• Disadvantage is high cost.

48. Sterilizing Filter
• Aqueous liquids sterilized by forced passage
through filter of porosity small enough to
retain any microorganism.
1) Membrane filters:
• Manufactured from variety of polymeric
material such as cellulose
diacetate, polycarbonate and polyester, as
disc.

49. Membrane Filter (Contd)
• Membrane made in 2 ways
1. Capillary pore membranes:
For viruses
2. Labyrinthine pore
membranes: Bacteria &
yeast
• Exact procedure for use
varies with form in which
filter is supplied.
• Filters may be supplied
with plastic holders pre
sterilized for single use, or
mounted in re-usable
holders and fitted to
filtration vessels.

50. Sterilizing Filter
2)Syringe filters:
• Membrane 13-25mm diameter.
• Fitted in syringe like holders
of stainless steel or
polycarbonate.
• Used for sterilization of small
volumes of fluid.
3)Vacuum and in- line filters:
• Membranes of 25-45 mm
diameter are used either with
in line filter holders of Teflon
or stainless steel and
aluminum.
• Used for sterilization of large
volumes of air and liquid.

51. 4) Pressure filtration:
• Large membranes, 100-
293 mm in
diameter, housed in
pressure filter holders.
• Production of pure water.
5) Air Filters:
• Large volume of air rapidly
freed from infection by
passage through HEPA
(High efficiency particle
arrester)

52. Air Filters (Contd)
• Principal use is to render
safe the air withdrawn from
an exhaust ventilated safety
cabinets used for work with
pathogens.
• To decontaminate air input
into laminar flow cabinet.
• Fitted with disposable pre
filter which reduces load
collected by main filter.
• Main HEPA should have
99.99% efficiency.

53. STERILIZATION BY RADIATION
• IONIZING radiation - γ
radiation from
radioactive elements
,usually Co60.,
E.g.. Sterilization of
Disposable Syringes.
Bacillus pumilis used for
testing.
• ULTRAVIOLET RAYS:
Mercury vapor lamps
emitting radiation in the
range of 250-260nm are
bactericidal & to a
lesser extent sporicidal.

54. References
• Mackie & McCartney Practical Medical
Microbiology 14 th edition
• Murray, Scot et al Text book of
medical microbiology
• Bailey & Scot, Diagnostic Medical
Microbiology Twelfth Edition
• Ananthnarayan and Paniker, Textbook
of microbiology, 8 th edition.