formulation and evaluation of small volume and large volume parenteral

1. FORMULATIO
N OF
SVP & LVP
P R E S E N T E D BY – S AG A R S . B H O R
G U I D E D BY – D R . S H I TA L B U TA N I

2. CONTENTS
• INTRODUCTION TO SVP & LVP
• ADVANTAGES
• DISADVANTAGES
• FORMULATION OF SVP & LVP
• PROCESSING OF PARENTRALS
• EVALUATION OF PARENTRALS
• REFERENCE

3. INTRODUCTION
• Parentrals preparation refers to injectable route of
administration
• It is derived from Greek word para (outside ) & enteron
(intestine)
i.e other than oral route .
Administered the drug into layers of skin

4. Primary Parentral Routes -
Routes Volume
administered
Sub-cutaneous 2 ML
Intramuscular 3 ML
Intradermal 0.5ML
Intravenous 1-100 ML

6. Advantages Of Parentral
Faster onset of action
Administration to unconscious patient
Avoid first pass metabolism
High bioavailability
Prolong action (depot)

7. Disadvantages –
Highly aseptic condition for manufacturing
Skilled person for req. for administration
Less patient acceptance
Pain at site of administration
Overdose can be fatal

8. Parentral
Small volume
parentral
Less than 100ml
contents
Large volume
parentral More than
100ml contents

9. SMALL VOLUME PARENTRAL -
• According to USP “ an injection that is packaged in containers
labelled as containing 100 ml or less contents “
• Generally contains drug formulation .

10. Large Volume Parentral
• Lvp mainly contains contents more than 100 ml
• LVP CONTAINS FOLLOWING
• Hyperalimentation Solution
large amount of nutrients to maintain a patient who is unable to take food
• Cardioplegia Solution
In heart surgery to help prevent ischemic injury to the myocardium during the time the
blood flow supply to the heart is clamped off & during reperfusion.,
• Solution are slightly alkaline & hypertonic in order to compensate for metabolic acidosis &
to minimize reperfusion injury resulting from tissue edema.
• Peritoneal Dialysis Solution
• Infused in abdominal cavity
• To remove the toxic substances from the body
• Irrigating Solutions
• Not given parentrally .
• Are intended to irrigate, flush, & aid in cleansing body cavities & wounds.

11. FORMULATION -
Antibacterial
agent
emulsifying
agent
Preservative
Buffers
Tonicity
adjuster
Antibacterial
Adjuvants
Aqueous
vehicle
Non –aqueous
vehicle
Vehicle
drug
API

12. Vehicle –
• For dissolution of solute and other formulation
additives.
• Types of vehicles -
Vehicle
Aqueous
•WFI
•Sterile WFI
•Bacteriostatic WFI
Water miscible
•Sesame oil
•Olive oil
•Cotton seed oil
Non-Aqueous
•Glycerine
•Ethanol
•PEG

13. • Sterile Water for injection –
– Sterile
– Non-pyrogenic
– pH 5.5
• Bacteriostatic water for injection –
– 0.9% benzyl alcohol added as preservative
– Applied in multiple –dose container
– pH 5.7

14. Antioxidant
• Prevent oxidation process
• Used alone or in combination with chelating agent
Eg. Ascorbic acid , tocopherol ,Butylated hydroxy anisole (BHA)
Butylated hydroxy toluene (BHT)
• Antimicrobial agents –
– prevent microbial growth in preparation
– added only in SVP and not in LVP
4 classes of Antimicrobial agents used
1.quaternary ammonium compounds
2. alcohols
3.esters
4.mercurial acids
Eg. Thiomersal , benzyl alcohol, phenyl mercuric nitrate & acetate

15. Tonicity Adjustment Agent –
Minimises following -
A) Tissue damage & irritation
B) Haemolysis of blood cells
C) Prevent electrolyte imbalance upon administration
Eg.Dextrose , Nacl ,
Tonicity is important for Suubcutaneous (SC) , Intradermal (ID) ,
Intramuscular route (IM)
Buffers
acetic acid , glutamic acid ,citric acid , phosphoric acid
surfactant
improve solubility
eg. Sorbital monooleate etc. tweens 20(16.7 HLB) & 80 (HLB 15)

16. Packaging
• Packaging is an art and science which involves preparing articles for transport ,
storage purpose
Ideal requirements of good package
1) They should hold the product without loss of contents (leakage ,spoilage )
2) should protect from environmental condition like temp. light , moisture
3) should not permeate gases
4) Matter of packaging material should not interact with formulation

17. • Container & closure system –
Container
Glass
Plastic

18. GLASS CONTAINERS –
• Generally employed with Solid rubber stoppers are used for container closure
system .
• Washed ,cleaned glass container should be held at minimum of 70 C to suppress
microbial growth.
• Pyrogens removed by subjecting to 210C for 3-4 hrs or 650 C for 60 sec.

19. Types Of Glass -

20. PLASTIC CONTAINER -
• Thermoplastic
– polymers soften upon heating & solidify upon cooling .
– Commonly used for parentrals.
• Thermosets –
– Chemically reactive
– Harden irreversibly by cross linking
– Epoxy , melamine resins , cross linked polyesters

21. COMMONLY USED POLYMERS IN
STERILE PRODUCTS -
 Polyethylene (PE)
 Polyvinyl chloride (PVC)
 Polypropylene (PP)
 Ethyl vinyl acetate (EVA)
 Polyamide(nylon)

22. TESTS FOR PLASTIC CONTAINERS
• 1. Leakage test
• 2. transparency test
• 3. water vapour permeability test
• Leakage test -
fill 10 conatiners with water & keep them in inverted position with intended closure
system for 24 hrs . Check for leakage after that period
• Transparency test –
fill 5 containers with nominal capacity with diluted suspension as described in IP
1966 . And cloudiness of each container Is checked as compared with container
filled with water
• Water vapour permeability test –
Fill five container with nominal volume and heat seal the bottle with aluminium foil .
Weigh accurately each container and keep them at 14 days at RH of 60+/- 5% and
temp in 20-25 C and reweight and loss in weight should not more than 0.2 %

23. LARGE VOLUME FLEXIBLE
CONTAINERS -
• Advantages –
– Durable & light weight
Bag collapses as it empties
• Material –
– Polyvinylchloride
– Ethylvinyl acetate films

24. BLOW FILL SEAL TECHNOLOGY (BFS)
• Technology originally developed in Europe
• Aseptic packaging of pharmaceutical products
• Machine fills volume from 0.1 ml to 1000 ml
Container
molding
Container
filling
Container
sealing

25. BFS PROCESS OUTLINE
• Polymer granules are fed to a machine hopper
• Within extruder, polymer is subjected to high temperatures (160'c)
and pressure (up to 350bar) and become molten.
• It is extruded through a die and pin set to form open-ended
tube of moltenpolymer known as PARISON,
• Parison - supported by sterile air that is fed into center of parison
through 3 sterilizing grade air filter,

26. • The nozzle assembly lowers into the parison until the nozzles form a
seal with the neck of the mould. Container formation is completed by
applying a vacuum on the mould-side of the container and blowing
sterile filtered air into the interior of the container.
• The patented electronic fill system delivers a precise dosage of product
into the container. The nozzles then retract into their original position.
• Following completion of the filling process, the top of the container
remains semi-molten. Separate seal moulds close to form the top and
hermetically seal the container. The moulds open and the container is
then conveyed out of the machine.
• Mold set in two halves moves over to the parison and closes around it
part moved to filling position and containers are sealed by second
mold set, which forms the neck and closure of BFS containers.

28. EVALUATION-
1. Sterility
2. Freedom from pyrogens
3. Freedom from particulate matter
4. Isotonicity

29. STERILITY TESTING -
• Sterility means complete absence of viable microorganisms.
• Test must be carried out in aseptic environment. (grade A laminar flow
)
• Exterior surface is cleaned with suitable antimicrobial agent .
• METHOD 1 – Membrane filtration
• Method 2 – Direct inoculation technique
Sterility
Membrane
filtration
Direct
inoculation

30. MEMBRANE FILTRATION
• Fluid thioglycolate media (FTG) – Anaerobic bacteria
• Soyabean casein digest media (SCD)- Fungi & aerobic bacteria
Transfer sub. onto
The membrane
Filter
Cut membrane in 2 pieces
Transfer 1in FTG & SCD media
Incubate for 14 days

31. DIRECT INOCULATION
Analyse
the results
Incubate
for 14
days
Transfer
substance
to media

32. PYROGEN TESTING
• Rabbit test
• LAL test
• Rabbit test –
– body temp of rabbits are measured upon injection of the formulation
– Temp recorded at 30 min interval between 1-3 hrs
– If any rabbit shows rise in temp more than 0.5 C then continue the test with 5 other
rabbits
– If not more than 3 rabbits out of 8 shows rise in temp by 0.5 C or more OR sum of temp
rise not more than 3.3 C then test passes .
• LAL test (Limulus Amebocyte Lysate)-
– Lysate derived from haemolymph cell of horseshoe crab limulus polyphemus
– Precipitation or gelation occurs upon addition of endotoxin containing sample .

33. Container Closure Integrity Test /
leaker test -
• Contents may leak outside & spoil the package
• The sealed container are dipped in colored solution of 0.5 – 1 % of methylene
blue & vacuum is applied . The solution inside leaked container shows blue
colour
• Particulate matter evaluation –
The parentral preparation should have particulate matter in range of 30-40
micrometer
USP states that all container should check visually inspected for visible particle
against dark background

34. • In lvp permitted limits of particulate matter is maximum of 50 particles
of 10 micrometer & 5 particles of 25 micrometer & no particle above
50 micrometer
• Coulter counter method & filtration method are used for monitoring
particulate matter

35. REFERENCE
• USP MONOGRAPH STERILE WATER FOR INJECTION
• TEXTBOOK OF REMINGTON
• Theory & practice of industrial pharmacy Leon Lachman , H. Liberman
• https://www.allfordrugs.com/large-volume-parenterals/
• PHOTOS FROM GOOGLE.COM

36. THANK YOU