Basic aspects of parenteral, advantages, disadvantages, types, formulation and evaluation

1. PARENTERAL
S

2. CONTENTS
1. Introduction
2. Advantages and disadvantages of parenteral
3. Routes of administration
4. General Requisites
5. Types
6. Components of parenteral
7. Quality control of parenteral
8. Sterilization
9. Packaging
10.Layout

3. Parenteral is the term derived from Greek word ‘Para’ and ‘Enteron’ meaning
to avoid the intestine.
They are sterile solutions, emulsions or suspensions of drugs.
According to the USP 24/NF19 parenterals are defined as “those preparations
intended for injection through the skin or other external boundary tissue, rather
than through the alimentary canal, so that the active substances can be
administered directly into a blood vessel, organ, tissue, or lesion.
WHAT IS A PARENTERAL?

4. ADVANTAGES
• Useful for patients who cannot take drug orally
• Rapid onset of action
• Useful for emergency conditions
• Sustained delivery of drug
• Bypass first pass metabolism
• Targeted drug delivery
• Useful in delivering nutrients, electrolytes or nutrients (TPN)
• Can be done in hospitals, ambulatory infusion centres and home health
care centres

5. • Invasive
• Irreversible drug effect
• Allergic reaction or sensitivity at the site of injection
• Utmost sterile conditions to be maintained and must be pyrogen free
• Skilled professionals are required
• Specialized equipment's, devices and techniques are required in
preparation and administration of parenteral
• Expensive
DISADVANTAGES

6. ROUTES OF ADMINISTRATION OF A PARENTERAL

7. INTRAVENOUS ROUTE
• Drug directly goes into the blood stream. Hence, rapid onset of action
• Predominantly used in critical and emergency areas
• Intravenous injections are administrated at a 15-25° angle
• The volume should not be greater than 1 litre
• Commonly used to provide essential nutrients for a critically ill patients
and for fluid and electrolyte replacement

8. INTRAMUSCULAR ROUTE
• In case of adults, intramuscular injections are given into inner and outer
gluteal maximus
• For children and some adults, IM injections are given to deltoid muscles
on the shoulder
• Drug in aqueous solution is rapidly absorbed while the drug in oily liquid
or in any suspension prolongs the release
• Typical needle is 22-25 gauge ½ to 1 inch
• IM injections are administrated at a 90° angle
• The volume should not be greater than 2 ml

9. SUBCUTANEOUS ROUTE
• Provides faster onset and longer duration of action when compared to
IV and IM injection
• Typical needle is 25-26 gauge 3/8 to 5/8 inch
• SC injections are administrated at a 45° angle
• The volume administered should not be greater than 1 ml into the site to
avoid pressure on sensory nerves causing pain and discomfort.
Ex: Insulin

10. INTRADERMAL ROUTE
• Drug is injected into top few layers of skin
• Small amount of drug is administered via this route and absorption is slower
• Common method used for allergy testing
• Used for diagnostic agents
• The injections are typically made with 26 gauge needle and small barrel
syringe

11. INTRACARDIAC ROUTE
• Drug is injected directly into heart muscles or ventricles
• Used in emergency
INTRAARTERIAL ROUTE
• Drug is injected directly into artery
• Given in emergency
Ex: Vasodilators and thrombolytic drugs

12. Route Injection site
Intravenous (IV) Vein
Intramuscular (IM) Muscle tissue
Intradermal (ID) Dermis of the skin
Subcutaneous (SC) Subcutaneous tissue of the skin
Intrathecal (IT) Subarachnoid space of the spinal cord
Epidural Epidural space of the spinal cord
Intra-arterial Artery
Intra-articular Joint space
Intracardiac Heart
Intraocular Eye
Intraperitoneal Peritoneal cavity

13. GENERAL REQUISITES
Stability Sterility Isotonicity
Free from
pyrogen, toxins
and foreign
particulates
Chemical purity

14. TYPES OF PARENTERALS
1. Small volume parenteral (SVP)
2. Large volume parenteral (LVP)

15. SMALL VOLUME PARENTERALS
• According to USP, SVPs are defined as injections packed in containers
labelled as containing 100ml or less
• If the SVP is a liquid that is used primarily to deliver medications, it is
packaged in a small plastic bag called a minibag of 50 - 100 ml (minibags
look like small plastic LVP bags). SVPs are also packaged as ampules,
vials, and prefilled syringes.
• Powdered drugs are supplied in vials and must be constituted (dissolved in
a suitable liquid) before being added to any solution.

16. TYPES OF SMALL VOLUME PARENTERALS
1. Solutions
2. Suspensions
3. Emulsions
4. Dry powder

17. 1. SOLUTIONS
• Helps deliver drug at a controlled infusion rate
• Commonly used solutions are 5% dextrose, normal saline, 45% normaline
saline or 5% dextrose (energy) with normal saline (sodium)
2. SUSPENSIONS
• Sterile, stable, pyrogen free, resuspendable, injectable, syringeable, isotonic
and non-irritating
• Administered either intramuscularly or subcutaneously
• Ex: Procaine penicillin G
• Contains 0.5 to 5% solids with particle size <5 micrometre
• Suspension provides increased resistance of drug to oxidation and
hydrolysis

18. 3. EMULSIONS
• Heterogenous dispersion of immiscible liquids
• Parenteral emulsions are rarely used since it is difficult to achieve a droplet
size of < 1 micrometer to prevent emboli in blood vessels
4. DRY POWDERS
• Overcomes instability of the drug, hence dispensed as powders to be
reconstituted before use
• Produced by freeze drying, aseptic crystallization and spray drying.

19. LARGE VOLUME PARENTERALS
• Packaged in glass bottles or in large volume flexible containers
• May contain greater than 100 ml to greater than 1 or 2 L
• Must be sterile, free from pyrogen and particulate matter
• No anti-microbial agents
• Isotonicity
• Classified into
1. Hyperalimentation solutions
2. Cardioplegic solutions
3. Peritoneal dialysis solutions
4. Irrigating solutions

20. 1. HYPERALIMENTATION SOLUTIONS
• Administration of large amount of nutrients into patients who cannot
take the food and medications orally
• Formulation generally consists of dextrose, amino acids, lipids,
electrolytes (Na, K, Cl, PO4) , and vitamins (water and fat soluble)

21. 2. CARDIOPLEGIC SOLUTIONS
• These solutions are used in heart surgery to prevent myocardium injury
during reperfusion and to maintain bloodless operative field
• Maintains diastolic arrest
• Administration in cold form
• Slightly alkaline

22. 3. PERITONEAL DIALYSIS SOLUTIONS
• Infused continuously into abdominal cavity, bathing peritoneum and
then are continuously withdrawal
• Helps in removing toxic substances from the body
• Aids and accelerates excretion
• Used in the treatment of acute renal insufficiency

23. 4. IRRIGATING SOLUTIONS
• Solutions that irrigate, flush and aid in the cleansing of body from wounds
• Certain IV solution such as saline may be used as irrigating solutions but
the solutions designed as irrigating solutions should not be used
parenterally.

24. Parameter SVP LVP
Volume 100ml or less 101-1000 ml
Route IV, IM or SC IV-LVP or nonIV-LVP
Dosage unit Single or multiple Single
Formulation Solution, emulsion,
suspension
Solution and o/w
nutrient emulsion
Isotonicity Not essential Must
Pyrogenicity Not essential Must
DIFFERENCES BETWEEN SMALL AND LARGE VOLUME
PARENTERALS

25. FORMULATION OF PARENTERALS
• Vehicles
• Stabilizers
• Wetting, suspending and emulsifying agents
• Buffers
• Antioxidants
• Antimicrobial agents
• Tonicity agents
• Protectants
• Inert gas

26. Vehicles
Stabilizers
Wetting,
suspending
and
emulsifying
agents
• Helps in solubilising drugs
• Must be free from microbial contamination
• Vehicles can be aqueous (sterile WFI, bacteriostatic WFI) or oily vehicle
• Ensures the stability of drug in the preparation
• Ex: Chelating agents like EDTA
• Wetting agent maintains the particle size
• Increases the drug solubility
• Ex: sorbital, tween 80

27. Buffers
Antioxidants
Antimicrobial
agents
• Tolerability of a formulation depends on its buffering capacity
• For the maximum physiological acceptability, the target pH is approximately pH 7.4
• Ex: Acetate buffer, TRIS buffer, citrate buffer, phosphate buffer etc.
• Maintain product stability by being preferentially oxidized and gradually consumed over
shelf life period of drug
• Ex: Chelating agents like EDTA, bisulphites, metabisulphites
• Inhibits the growth of microbes introduced accidentally during withdrawal of multiple
doses
• Preservatives may be added to single dose parenterals which aren’t terminally sterilized.
• Ex: Parabens, Benzalkonium chloride, phenol etc.

28. Tonicity
adjusting
agents
Protectants
Inert gases
• The possibility that the product may penetrate red blood cells and cause hemolysis is
greatly reduced if the solution is isotonic with the blood
• Hypotonic solution causes cells to swell while hypertonic solution causes hemolysis
• Ex: Sodium chloride (0.9%), dextrose (3.75 to 5%), mannitol(0.4 to 2.5%)
• Protects the loss of activity of drugs due to stress
• Prevents the loss of AI by adsorption to process equipment's or primary packaging
materials
• Mainly used in protein formulations. Ex: sucrose, glucose, lactose, maltose etc.
• Enhances the product integrity of oxygen sensitive drugs by displacing the air in the
solution with nitrogen or argon
• Purging the container with nitrogen or boiling the water to reduce dissolved oxygen is
more effective

29. EVALUATION / QUALITY CONTROL OF PARENTERALS
1. Leakage test
2. Clarity test
3. Sterility test
4. Pyrogen test
5. Content uniformity test

30. 1. LEAKAGE TEST
Filled and sealed ampoules
Dip in 1% methylene blue solution under negative pressure in a vacuum
chamber
Observe the color of the sample after and before the test
Color change indicates the leakage due to defective sealing
4 types of leakage test
 Visual inspection
 Dye test
 Bubble test
 Vacuum ionization

31. 2. CLARITY TEST
Also referred as particulate matter monitoring.
4 ways:
 Microscopic count
 Light obstruction
 Visual method
 Coulter counter method
Particle size (µm) Maximum number of particles/ ml
10 50
25 5
50 Nill

32. Visual method
Microscopic
count
Light
obstructive
method
• Ampoules are placed against dark background to observe light particles and against
white background to observe dark particles
• Sample solution is filtered using membrane filters
• Particles are observed under the microscope using 100x magnification
• Using the light beam instrument, particles are observed crossing the light beam
• Particles are then measured and counted
Coulter
counter
method
• Based on the principle that there will be an increased resistance as a particle approaches
and passes through the orifice
• This method requires destruction of product unit since an electrolyte is added to the
preparation before the evaluation

33. 3. STERILITY TEST
• Defined as microbiological test applied to sterile product to check the
products are manufactured and processed as per GMP specifications.
• It is a destructive test.
• 2 methods
i. Direct inoculation
ii. Membrane filtration
• Fluid thioglycolate medium and soyabean casein digest medium are the two
media used in sterility testing of a parenteral.

34. DIRECT INOCULATION METHOD
• Involves direct inoculation of required volume of samples into two test
tubes containing FTGM and SCDM
• Volume of the preparation under evaluation should not be greater than 10%
of the volume of medium
• Incubate the inoculated media for not less than 14 days

35. Minimum quantity to be used for each medium
Quantity per container Minimum quantity to be used for each
medium
Liquids
1. Less than 1 ml The whole contents of each container
2. 1-40 ml Half the contents of each container but
not less than 1 ml
3. Greater than 40 ml but less than 100 ml 20 ml
4. Greater than 100 ml 10% of the contents of each container but
not less than 20ml
Antibiotic liquids 1 ml

36. Minimum number of items to be tested
Number of items in the batch Minimum number of items to be tested
for each medium
Not more than 100 containers 10% or 4 containers whichever is greater
More than 100 but not more than 500
containers
10 containers
More than 500 containers 2% of 20 containers (10 containers for
LVPs) whichever is the less

37. MEMBRANE FILTRATION METHOD
• This method involves filtration of sample through membrane filters (0.45µ)
under the vacuum
• Membrane is cut into 2 halves after filtration and is placed into FTGM and
SCDM respectively
• The medium is incubated for not less than 14 days.

38. Interpretation of results
• If the medium turns turbid and the microbial growth can not be visually
determined, 14 days after the beginning of incubation, transfer portion of
medium into fresh vessels of the same medium and then incubate for not
less than 4 days.
• If there is no evidence of microbial growth, complies the sterility test.
• If there is microbial growth in the medium, the preparation is not sterile.

39. 4. PYROGEN TEST
• Pyrogens are fever inducing organic substances having endogenous or
exogenous nature
• There are 2 tests basically performed to detect and quantify the pyrogens
i. In vivo pyrogen test (Rabbit test)
ii. In vitro pyrogen test (LAL test)

40. i. In vivo test (Rabbit test)
Principle: Measurement of rise in body temperature evoked in rabbits by the
injection of sterile solution of the sample being examined.
Selection of animals: Healthy animal (NLT 1.5kg), fed with balanced diet and
no antibiotics. A rabbit shouldn’t be used in pyrogen test if it has been used in
a negative pyrogen test in the preceding 3 days.

41. Preliminary test (SHAM test)
• IV injection of sterile pyrogen-free saline to exclude any animal showing an
unusual response to the trauma of injection.
• Any animal showing a temperature variation greater than 0.6°C is not used
• All glassware's, syringes, needles must be pyrogen free by heating at 250°C
for not less than 30 min.
• Warm the pyrogen free solution up to 38.5°C.

42. Rabbit pyrogen test
• Rabbits must be healthy and mature of any sex
• Must be individually housed between 20 and 23 °C and shouldn’t vary
more than +/- 3°C
• The sample is injected slowly into the marginal veins of the ear of each
rabbit over a period not exceeding 4 min
• Record the body temperature of each rabbit at half hour intervals for 3
hours after injection
• The difference between the initial and maximum temperature which is the
highest temperature recorded for a rabbit is taken to be its response.

43. Interpretation of result
Number of rabbits Individual
temperature rise
(°C)
Temperature rise
in group
Test result
3 0.6 1.4 Pass
If above 3, should
not pass 3+5 rabbits
0.6 3.7 Pass
If above test doesn’t pass, the sample is said to be pyrogenic.

44. ii. Limulus Amoebocyte lysate (LAL) test
• To detect and quantify the endotoxins of gram negative bacteria
• Reagent used: Amoebocyte lysate from horse shoe crab (Limulus
polyphemus or Tachypleus tridentatus)
• Principle: Primitive blood clotting mechanism of the horse shoe crab
• The addition of solution containing endotoxin to lysate solution produces
turbidity
• The endotoxin reference standard is freeze dried
• Involves bleeding adult crabs into an anticlotting solution, washing and
centrifuging to collect the amoebocytes
• Lysing in 3% NaCl, washing the lysate
• lyophilization for storage.

45. Test performance
• Equal volume of LAL reagent and test solution (0.1ml) are mixed in a
depyrogenated test tube
• Incubate at 37°C for 1 hour
• Remove the tube, invert to 180° and observe the result.

46. Advantages of LAL test
• Faster results (60 min)
• Greater sensitivity and less variability
• More reliable results
• Useful in radiopharmaceuticals, blood products and cytotoxic agents

47. 5. Content uniformity test
• 30 sterile units selected from each batch
• Weight of 10 individual sterile unit is measured and weight of the units
after removing the contents is also noted to calculate the net weight
• Net weight = Gross weight – empty sterile unit weight
• Dose uniformity is met if the amount of active ingredient is within the
range of 85 to 115% of label claim
• If one unit is outside this limit, and none of the sterile unit is outside the
range of 75-125%, an additional 20 sterile unit should be tested
• The sterile units meet the criteria if NMT one unit is outside the range of
85-115%, no unit is outside the range of 75-125%.

48. STERILIZATION
Sterilization process Biological indication
Moist heat sterilization Spores of Bacillus stearothermophilus are
killed
Dry heat sterilization Spores of Bacillus pumilus
Ionization radiation sterilization Spores of Bacillus pumilus and Bacillus
subtilis
Gaseous sterilization Spores of Bacillus subtilis
filtration Spores of Serratia marcescens and
Brevundimonas diminuta

49. CONTAINERS AND CLOSURES
Characteristics
• No interaction between containers and the contents
• Should withstand high temperature especially during sterilization
• Should protect the contents from harmful radiation
• Should be suitable for repeated use and easy cleaning
• Containers made up of glass and plastic are widely used
• Natural and synthetic rubbers are usually used as closures

50. Type General description Type of test General use
I Highly resistant
borosilicate glass
Powdered glass Buffered and
unbuffered aqueous
solution. All other uses.
II Treated soda lime glass Water attack Buffered aqueous
solution (pH<7), dry
powders, oleaginous
solutions
III Soda lime glass Powdered glass Dry powders,
oleaginous solutions
Non parenteral General purpose soda
lime glass
Powdered glass Not for parenterals. For
tablets, oral solutions,
suspensions, ointments
and external liquids
1. GLASS

51. 2. PLASTIC CONTAINERS
Thermoplastic Thermosetting plastic
On heating, these soften to a viscous fluid
which again hardens on cooling
When heated, they may become flexible
but not fluid
Hardness depends on degree of cross
linkage or intermolecular attraction
They are hard and brittle at room
temperature because of high degree of
cross-linking
Ex: Polyethylene, polystyrene, PVC,
PMMA, polyamide, polycarbonate and
polypropylene
Ex: Phenol-formaldehyde
Urea-formaldehyde
Melamine-formaldehyde

52. LAYOUT OF PARENTERAL PROCESSING

53. Conclusion
• Parenterals are sterile preparations administered directly into blood vessel,
organ, tissue or a lesion.
• They can be administered through intravenous, subcutaneous, epidural,
intramuscular, intrcardial routes etc.
• They need to be sterile, pyrogen free, stable and isotonic
• They are of two types small volume and large volume parenterals and can
be formulated as suspensions, emulsions, solutions etc.
• The parenterals can be evaluated by in vitro and in vivo methods
• They must be produced under aseptic environment
• The parenterals are usually filled in glass or plastic containers.

54. References
• file:///C:/Users/hp/Downloads/A_REVIEW_ON_PARENTERAL_PRODU
CTION_TECHNO.pdf
• Parenteral drug delivery – A review
• The-pearson-guide-to-gpat-and-o-umang-h-shah-srj third edition
• https://e-
currentscience.com/storage/app/archive/pdf/czcx1ekbW0o8rymgyPd6fLIY
UeI8snpaCBX35jDa.pdf