small volume parentrals

1. SMALL VOLUME PARENTRALS
PRESNTED BY:
KARTHIK SWAMY
B.M
(DEPARTMENT OF
PHARMACEUTICS)
UNDER THE
GUIDANCE OF:
DR.Y.ANAND
KUMAR

2. PARENTERALS
Sterile pyrogen-free preparations intended for administration
by injection under or through one or more layers of skin or
mucous membranes.
TYPES
1) Small Volume Parenterals - Volume ranges from 1-30 ml .
May be given single dose or multiple dose.
2) Large Volume Parenterals- Volume ranges from 100-1000
ml. Mostly given as single dose

3. Usually range 1-30 ml in volume.
Mostly given as multiple doses.
Different types are:
Ampoules
Vials
Dry powders
Prefilled syringe
SMALL VOLUME PARENTRALS (SVP):

4. AMPULE

5. VIALS

6. PREFILLED
SYRINGE

7. Manufacturingof small volumeparenterals
Formulation additives/excipients
Criteria for the selection of excipient
 Influence of excipients on the overall quality, stability, and
effectiveness of drug product.
 Compatibility of excipients with drug and the packaging
system.
 Compatibility of excipients with the manufacturing process.
 The amount or percentage of excipients that can be added to
the drug product.

8.  Vehicles
Aqueous vehicles
 Water for injection
 Water for injection is the major vehicle of choice for therapeutic
agents, freely soluble (for the preparation of parenteral solutions),
low aqueous solubility (for the preparation of parenteral
suspensions) and the external phase of parenteral emulsions.
Water for injection should posses the following properties,
 Appearance- It should be clear, odourless and having defined pH
range 5-7.
 Purity- Limits on the mass of ions, heavy metals and oxidisable
compounds and also on the total amount of dissolved solids <10
ppm

9.  Sterility- Water for Injections USP is non-sterile and is used in
the preparation of parenterals that will be terminally sterilized.
 Pyrogens- Water for injection must be free of pyrogens and are
effectively removed from water using either distillation or reverse
osmosis. Removal of pyrogens from the storage containers is
typically performed by heating the container at either 2500C for
30-45 minutes or at 1800C for 3-4 hours.
 Sterile water for injections USP
 Bacteriostatic Water for Injections USP
 Sodium chloride injection USP
 Bacteriostatic sodium chloride injection USP

10. Non Aqueous vehicles
 Non-aqueous vehicles are employed for the
production of,
 Non-aqueous vehicles should posses following
properties,
Examples
 Fixed vegetable oils- Corn oil, Castor oil,etc
 Other examples- Ethyl oleate, Isopropyl myristate,etc

11. Cosolvents
Cosolvents are employed whenever the solubility of the
drug in water (or occasionally in oil-based vehicles) alone
is insufficient for the required application.
Examples- Glycerol, Ethanol

12. Buffers and pH adjusting agents
Buffers are added to a formulation to adjust and
stabilize pH and optimize drug solubility and stability,
for parenteral preparations, it is desirable that the
product pH be close to physiologic pH. Selection of a
buffer concentration (which contributes to the ionic
strength of the formulation) and a buffer species is
important.
Examples with pH range viz., Sodium Acetate 3.8–5.8,
Ammonium sulfate 8.25–10.25, Ascorbate 3.0-5.0,
Benzoate 6.0–7.0, Bicarbonate 4.0-11.0, etc.

13. Preservatives
Preservatives are incorporated into parenteral
formulations whenever,
•The product is a multidose preparation. In this, several
separate doses will be removed from the same
container; the inclusion of preservatives is necessary to
control microbial growth due to microbial introduction
into the product.
•The product has not been terminally sterilized.
Examples viz., Benzalkonium Chloride (0.01%-0.02 %
w/v); Benzyl alcohol (0.75-5 %); Chlorobutanol (0.25-
0.5 %); m-Cresol (0.1- 0.315%); etc

14. Antioxidants
•Many drugs including phenothiazines, polyene antimicrobial
agents, steroids, morphine and tetracyclines are susceptible to
degradation by oxidation, a process involving the addition of an
electronegative atom or radical or the removal of an electropositive
atom, radical or electron.
•Antioxidants are included in parenteral formulations to slow
down or inhibit oxidative degradation of therapeutic agents.
•Example viz.;Acetone, Sodium bisulfate(0.2-0.4%w/v), Ascorbyl
palmitate, Ascorbate [(sodium/acid)0.1-4.8%w/v], Sodium
bisulfite (0.02-0.66%w/v), Butylated hydroxy anisole
(BHA)(0.00028-003%w/v), Butylated hydroxy toluene
(BHT)(0.00116–0.03%w/v), etc.

15. Chelating agents
Sequester heavy metals to prevent the catalysis of
oxidation reaction, Furthermore, chelating agents, react
with the metal ions to form stable water soluble
complex.
Examples viz., Calcium disodium EDTA, Disodium
EDTA, Sodium EDTA,etc.

16. Cryoprotectants and Lyoprotectants
Excipients that are preferentially excluded from the
surface of the protein are the best cryoprotectants, and
excipients that remain amorphous during and after
freeze-drying serve best as lyoprotectants.
Examples viz.,
Sugars (non-reducing)- Sucrose or Trehalose, Lactose ;
Amino acids- Glycine, Lysine; Polymers- Liquid
polyethylene glycol or dextran,etc.

17. Tonicity adjusting agents
 Tonicity adjusting agents are used in many parenteral and
ophthalmic products to adjust the tonicity of the solution.
 The agents most commonly used are electrolytes and mono or
disaccharides. Typically Sodium chloride or Dextrose is used for
this purpose.
 The tonicity of parenteral formulations is an important design
criterion. In the presence of a hypotonic solution, red blood cells
will swell (due to water entry into the cell) and eventually burst
(termed haemolysis) whereas, in the presence of a hypertonic
solution, water will leave the red blood cells, leading to crenation.

18. There are different methods by which the mass of these
compounds required to render the solution isotonic may be
calculated viz., Gram-molecular concentration method; Freezing-
point depression of the solution method; Sodium chloride equivalent
method; Graphical method.
Gram-molecular concentration method
 The gram-molecular concentration refers to the number of moles
of substance in 100 grams of solvent.
 For example if 1 gram molecule (mole) of a non-ionic compound
is dissolved in 100 grams of water, the gram-molecular
concentration is 1%.
A solution is isotonic whenever the gram-molecular concentration
is 0.03%.

20. EVALUATIONS
Leaker's Test
Sterility Test
Clarity Test
Pyrogen Test

21. It is performed by completely submerging the sealed ampule in a
deeply coloured dye solution.
Generally 1% methylene blue solution is used
The ampules if not sealed properly, the dye solution present outside
the ampules will enter into the ampules and make the solution coloured.
CLARITY TEST:
The parenteral product to be evaluated is placed against a white and
black background with the contents set in motion in swirling action.
It is kept in that motion until any particle becomes visible or not.
Care is to be taken to avoid any air bubbles
LEAKERS TEST

22. Important to check if the product meets the requirements
of sterility according to the official books or not.
methods:
-The direct transfer of the samples to sterile culture media.
-The membrane filtration procedure
STERILITY TEST

23. Samples of production batch are tested in rabbits for the presence of
pyrogens.
2 stages:
1) Sham test
2) Main test
1) Sham test:
If the animals are being used for the first time in pyrogen testing, then
condition the animals for 1-3 days by injecting 5mg/kg body weight of
pyrogen free solution IV
.
Maintain animals like that for 18 hrs in room maintained at a temp of 3ºC.
Record the temperature of the animals beginning at least 90 mins before
injection and continuing for 3 hrs after injection.
Any animal showing variation of 0.6ºC or more must not be used for main
test.
PYROGEN TEST

24. 2) Main Test:
Determine the control temperature of each rabbit by recording the
temperature not more than 30 mins prior to injection of test solution.
Inject into an ear vein of each rabbit 10 ml of the test solution per kg body
weight, completing each injection within 10 mins after start of
administration.
The test solution must be warmed upto 37±2ºC.
Record the temperatures at 1, 2 and 3 hrs subsequent to the injection.
Following are the requirements for passing the test:
1) Individual rise in temperature of 0.6ºC with respect to control and sum of
3 individual rabbits does not exceed 1.4ºC, the sample passes the test.
2) If anything above the above mentioned requirements, continue the test
with 5 other rabbits.
3)Individual rise in temperature not more that 0.6ºC and sum of all eight
does not exceed 3.7ºC, the sample passes the test

25. THANK YOU