This document provides information about small volume parenterals (SVPs), which are injections packaged in containers of 100ml or less. It discusses the formulation, ingredients, containers, sterilization, and manufacturing of SVPs. Specifically, it describes that SVPs can be aqueous or non-aqueous solutions administered intravenously. It also outlines various additives used in SVP formulations, including vehicles, solvents, buffers, and preservatives. The document discusses sterilization methods like heat, filtration, and radiation. It provides details on terminal sterilization and blow-fill-seal technology for SVP production.

1. Small Volume Parenteral (SVP)

2. According to USP : “ an injection that is packaged in containers
labelled as containing 100 ml or less”.
All the sterile products packaged in vials, ampoules, cartridges,
syringes, bottles or any other container that is 100ml or less fall
under the class of SVP.
SVP aqueous solutions can be administered by intravenous route
because of local irritation. Small volume parenteral products can be
formulated and packaged in several ways and include a wide variety
of products like :
Small Volume Parenteral (SVP)

3. Advantages:
 It provides rapid onset of action
 It provides immediate therapeutic action
 It can be administered accurate dose.
 It can be given to patients who cannot take oral
medication.
 It minimize the first pass effect.
 It provides more bioavailability

4. Disadvantages:
 Pain upon injection.
 Generally need medical help for administration (like physician or
nurse usually in hospital or clinic)/Trained person is required.
 It requires strict adherence to aseptic procedures in production,
packaging and administration.
 Chances of improper dosing are more.
 Danger of blood clot formation is there.
 Drug can not be recovered in adverse conditions.
 More expensive than other dosage forms.
 Traumatic injury from the insertion of needle.
 Impossible to retrieve if adverse reaction occurs

5. Formulation of SVP :
Aqueous vehicle :
Types:- purified water, WFI, sterile WFI,
bacteriostatic WFI, sterile WF Irrigation.
Preparation :- Distillation , ion exchange or reverse
osmosis.
Except purified water all are pyrogen free
Non aqueous vehicle :
Because of safety
purity
biocompatibility

6. Several SVPs are marketed as oily solutions.
The oil must be vegetable in origin (sesame, olive, or
cottonseed oil).
Product USP Oil
Ampicillin(suspension) Vegetable
Diethyl stilbestrol Sesame, Cotton
Epinephrine(suspension) Sesame
Penicillin G procaine Vegetable
(suspension)
Co solvents :-
Are used to increase the stability of poorly soluble drug in
water and prevent drug chemical degradation by hydrolysis
Ex propylene glycol or in combination with ethanol and
polyethylene glycol.

7. INGREDIENTS OR ADDTIVES
The USP includes in this category all substances added to a
preparation to improve or safeguard its quality. An added
substance may:
 Increase and maintain drug solubility.
 Provide patient comfort by reducing pain and tissue irritation.
 Enhance the chemical stability of a solution.
 Enhance the chemical and physical stability
 Minimize protein interaction with inert surfaces, such as glass
and rubber and plastic.
 Protect a preparation against the growth of microorganisms.

8.  It must be non toxic in quantity administered to the patient.
 It should not interfere with therapeutic efficacy nor with the
assay of active therapeutic compound.
 It must be prevented from adversely affecting the product
 Antioxidants
 Stabilizers
 Buffers
 Chelating agent
 Protectants
 Solubilizing agent
 Surfactants
 Tonicity adjusting
 Cryoprotectants and Lyoprotectants
Note : LVP is not contain bactericide so from vehicle
part exclude BWFI and Anti-microbial agent.

9. Containers & closures
1.Glass
2.Plastic
3.Rubber closure with Aluminium caps
Small volume parenterals: less than 100ml
Large volume parenterals : more than 100ml
E,g.
Ampoules( single dose )
Vials( multiple dose)
Cartridges
Automatic injector

10. Packaging materials: Glass ,Plastic, Rubber
 Sealing Ampoules are unique in that the primary and
secondary seal are the same.
 Ampoules are sealed by melting a portion of glass in a
flame.
 Pull seal – Slow, Reliable, powder or other types with
wide opening Roll or Tip seal
Packaging :

11. STERILIZATION
 Steam sterilization
 Dry heat sterilization
 Sterilization by filtration
 Gas sterilization
 Sterilization by ionizing radiation

12. Moist Heat Sterilization
 Bacterial death by moist heat is due to denaturation and
coagulation of essential protein molecules (enzymes)
and cell constituents.
 It can be used for a large number of injections,
ophthalmic solutions etc.
Methods used:
 Autoclave
 Tyndallization

13. Autoclaving used to sterilize anything, which is not injured by
steam and high temperature of sterilization. These include
aqueous parenteral solutions e.g. distilled water, saline
solutions etc.
Tyndallisation essentially consists of heating the substance to
boiling point (or just a little below boiling point) and holding it
there for 15 minutes, three days in succession. After each
heating, the resting period will allow spores that have survived
to germinate into bacterial cells; these cells will be killed by
the next day's heating.

14. Dry Heat Sterilization
The killing of microorganisms by heat is a function of the time-
temperature combination used. If the temperature is increased then
the time required for killing all the bacteria will be decreased.
The vital constituents of cells such as proteins (enzymes) and
nucleic acids are denatured by oxidation.
Cycles recommended as per BP 1988 are:
 A minimum of 1800C for not less than 30 minutes.
 A minimum of 1700 C for not less than 1 hour.
 A minimum of 1600 C for not less than 2 hours.
Dry heat is used to sterilize glass ware ( e.g., glass syringes etc.

15. Gas sterilization
This process involves exposure of materials to
sterilizing gases such as ethylene oxide, formaldehyde,
glutaraldehyde, propylene oxide.
 Ethylene oxide is the only gas that is successfully
used on a large scale of industrial and medical
applications. It works by alkylation.

16. Different types of radiation used for sterilization are:
 Ultraviolet radiation
 Gamma radiation
 Infrared radiation
 X-rays
 Alpha and beta radiation
Only a narrow range of wavelength (220 to 280 nm) of UV is
effective in killing micro-organisms, and wavelengths close to
253.7 nm are the most effective.
Radiation from the radioactive isotope of Cobalt 60, is used as a
source of gamma emission.
Radiation sterilization causes damage to DNA and results in cell
death.
Sterilization by Radiation

17. This method is used for sterilizing thermo-labile solutions,
which will otherwise be degraded by other conventional heating
methods.
The drug solutions are passed through the sterile bacteria proof
filter unit and subsequently transferring the product aseptically
into the sterile containers which are then sealed.
Different types are :
 Sintered glass filter
 Seitz filter
 Ceramic filter
They are suitable for sterilizing aqueous and oily solutions but
not for organic solvents such as alcohol, chloroform etc.
Sterilization by filtration

18. Terminal Sterilization
Product is sterilize in final container
It refer that the finished product should withstand with
steam sterilization cycle for 15 minutes.
Terminal Sterilization help to assure the sterility of the
finished product.
LVP : Moist and dry heat sterilization process are preferred.

19. Blow Fill Seal Technology.
It is most widely used and accepted by US FDA.
Polypropylene granules are heated at 2000C to form tube
shaped prison.
Prison reaches the mould forming container by the sterile
compressed air
Fill nozzle known as mandrel fills the liquid in the
container.
Followed by sealing neck and filled container is resealed
from the mould.
It takes 10-15 sec of time to produce one container.

20. Manufactured facilities of parenterals
The production area where the parenteral preparation are
manufactured can be divided into five sections:
Clean-up area
Preparation area
Aseptic area
Quarantine area
Finishing & packaging area

21.  Parenteral suspension is a dispersed, multi-phased,
heterogeneous system of insoluble solid particles intended
principally for intramuscular and subcutaneous injection.
Because a delicate balance of variables is required in order
to formulate a suitable product, a suspension is one of the
most difficult parenteral forms to prepare.
 Such a product must not cake during shipping and storage
and should be easy to suspend and inject through an 18 to
21 gause needle throughout its shelf life.
Suspension

22.  To achieve these goals it is necessary to control the
crystallization, particle size reduction and sterilization of the
drug substance.
 Suspension give prolong drug release particle size of drug
should be small and uniform.
 Suspension require following additives wetting agent,
suspending agent, buffering agent, preservative, antioxidant,
ionicity agents

23. Example of ingredients used in aqueous
parenteral suspensions
 Suspending agent
Gelatin, mannitol, povidone
 Surfactants
Lecithin, polysorbate 80.
 Solubilizing agents
Propylene glycol
 PH adjustment
Citric acid, sodium citrate.

24. Two basic method are used to prepare parenteral
suspension:
 Sterile vehicle and powder are combined aseptically.
 Sterile solutions combined and crystal formed in
situ.
Problem encountered in suspension formulation are:
 Settling and caking.
 Polymorphic transformation.
 Crystal growth.

25.  An emulsion is a heterogenous dispersion of one immiscible
liquid in another.
 This inherently unstable system is made possible through the use
of an emulsifying agent, which prevent coalescence of the
dispersed droplet.
 Parenteral emulsion are rare because it is necessary (and difficult)
to achieve stable droplet of less than 1micron meter to in prevent
emboli in blood vessels and it is not usually necessary to achieve
an emulsion for drug administration.
 Formulation options are severely restricted through a very limited
selection of stabilizers and emulsifiers primarily due to the dual
constraints of autoclave sterilization and parenteral injection.
EMULSIONS

26. Parenteral emulsions are used for several purposes, including :
 Water-in-oil emulsions of allergenic extracts
 Oil-in-water sustained-release depot preparations
 Oil in-water nutrient emulsion.

27. It is also known as lyophilization i.e. system is made solvent
loving for removing the same.
Principle:
In freeze drying, water is removed from the frozen state by
sublimation, i.e., direct change of water from solid into vapour
without conversion to a liquid phase.
Solid-liquid- vapour equilibrium phase diagram of water is
useful to decide the experimental conditions.
 The drying is achieved by subjecting material to temperature
& pressure below the triple point.
 Under this conditions, any heat transferred is used as latent
heat & ice sublimes directly into vapour state.
Freeze drying

28. Construction :
Freeze dryer consist of
 Drying chamber in which trays are locked
 Heat supply in the form of radiation source heating coils
 Vapour condensing or adsorption system
 Vacuum pump or steam ejector or both.

29. Working:
The working of freeze dryer consist of following steps.
Preparation & pretreatment:
 The volume of solution introduced into the container is limited by
its capacity. Therefore pretreatment is essential. The solutions are
preconcentrated under the normal vacuum tray drying. This
reduces the actual drying by 8 to 10 times.
Prefreezing to solidify water:
 Vials, ampoules or bottles in which the aqueous solution is
packed are frozen in cold shelves (- 50ᵒC). The normal cooling
rate is about 1 to 3 Kelvin/ minute so that large ice crystals with
relatively large holes are formed on sublimation of ice. This is
also responsible for giving a porous product.

30.  The freeze drying is achieved by subjecting material to
temperature & pressure below the triple point of water at
which solid, liquid and vapour all co-exist in equilibrium.

31. Primary Drying:
 Removing the solvent (ice) from the product, by evacuating
the chamber, usually below 100 μm Hg, and subliming the
ice onto a cold, condensing surface at a temperature below
that of the product, the condensing surface being within the
chamber or in a connecting chamber.
It means sublimation of ice under vacuum. The temp. &
pressure should be below the triple point of water i.e.
0.0098ᵒC & 4.58 mmHg for sublimation, when water is alone
present.

32.  When a solution of a solid is dried, the depression of freezing
point of water occurs. Hence, it is essential that the temperature be
brought below the eutectic point.
 The pressure & temp. at which the frozen solid vaporizes without
conversion to liquid is referred to as the eutectic point.
 Depending on the drug substances dissolved in water, the eutectic
point is determined. The usual range is from -10ᵒC to -30ᵒC.
 Heat (About 2900 kilojoules/ Kg) is supplied which transfer as
latent heat & ice sublimes directly into vapour state.
 As the drying proceeds, thickness of dried solids increases.
Primary drying stage removes easily removable water, about 98%
to 99%.

33. Secondary Drying:
 It is removable of residual moisture or bound water under high
Vacuum. The temp. of solid is raised to as high as 50 to 60ᵒC but
vacuum is lowered below that is used in primary drying. The rate
of drying is very low .
 The temperature for secondary drying should be as high as
possible, without causing any chemical degradation of the active
ingredient.

34. Advantages of Freeze-Dried Products
Product is stored in dry state-few stability problems.
Product is dried without elevated temperatures.
Good for oxygen and/or air-sensitive drugs
Rapid reconstitution time
Constituents of the dried material remain homogenously
dispersed.
Product is process in the liquid form.
Sterility of product can be achieved and maintained

35. Disadvantages of Freeze-Dried Products
Volatile compounds may be removed by high vacuum
Single most expensive unit operation
Stability problems associated with individual drugs
Some issues associated with sterilization and sterility
assurance of the dryer chamber and aseptic loading of
vials into the chamber