The document discusses parenteral therapies, defining them as sterile drug solutions administered outside the intestine, highlighting their advantages like quick action and disadvantages such as cost and risk of complications. It classifies them into small volume parenterals (SVPs) and large volume parenterals (LVPs), detailing their characteristics, manufacturing processes, formulation considerations, and various testing methods to ensure sterility and safety. Additionally, it explains the importance of physiological compatibility and the evaluation methods for ensuring quality in parenteral preparations.

1. Large and small
volume
parenterals
By- Rahul rangila
M.Pharmacy 1st
sem
(Pharmaceutics)
Lord Shiva College of Pharmacy

2. Content
Definition
Advantages
Disadvantages
Classification
Physiological consideration
Manufacturing consideration
Manufacturing
Evaluation

3. PARENTERALS
• Parenterals are sterile solutions or suspension of a drug in
aqueous or oily vehicle
• The term derived from two Greek words,
Para → outside; Enteron → intestine (i.e. beside the intestine)
• Parenterals drugs are administered directly into the veins,
muscle, under the skin , or more specialized tissues such as
spinal cord.

4. ADVANTAGES
• Quick onset of action
• Useful for unconscious and vomiting patients
• Avoid first pass metabolism
• Can inject drug directly into a tissue (target drug
delivery)
• Useful for delivering fluids, electrolytes, or nutrients.
• Complete bioavailability.

5. DISADVANTAGES
• Difficult to reverse after administration.
• Expensive cost of production, storage, and administration
• Many parenteral drugs cannot be self-administered,
requiring dependence on healthcare services.
• Sensitivity or allergic reaction to the site or action
• Dosage miscalculations can result in toxicity or other
complications.

6. CLASSIFICATION
1. Small volume parenterals (SVP)
2. Large volume parenterals (LVP)

7. Small Volume
Parenterals (SVPs)
Volume: Usually less than 100 mL.
Characteristics:
• Administered as a single dose.
• Does not require further dilution before use.
• Typically used for injections (IV, IM, SC, or ID).
Examples:
Ampoules, vials, Vaccines and Hormonal preparations.

8. Large Volume
Parenterals (LVPs)
Volume: Usually 100 mL or more.
Characteristics:
• Administered intravenously over an extended period.
• Used for fluid replacement, electrolyte balance, or parenteral nutrition.
• Packaged in bottles or flexible bags.
Examples:
Intravenous fluids like 0.9% saline, dextrose solutions, Total parenteral nutrition
(TPN) and Ringer’s lactate solution.

9. Types of small volume
parenterals (SVPs)
• Solutions
• Suspensions
• Emulsions
• Dry powder

10. Types of large volume
parenterals (LVPs)
• Intravenous Fluids
• Parenteral Nutrition
• Plasma Volume Expanders
• Irrigation Solutions

11. Comparison
Parameters
Small Volume Parenterals
(SVPs)
Large Volume Parenterals (LVPs)
Volume <100 ml >100ml
Purpose Single-dose therapy
Prolonged infusion, hydration,
nutrition
Administration IV, IM, SC, ID IV
Packaging
Ampoules, vials, prefilled
syringes
Bottles, flexible bags
Examples Vaccines, insulin, antibiotics Saline, dextrose, parenteral nutrition

12. PHYSIOLOGICAL
CONSIDERATIONS
• pH Compatibility : The pH of the preparation must be compatible with the
physiological pH (7.35–7.45) to avoid irritation or tissue damage.
• Sterility : Parenteral preparations bypass natural barriers like the skin and
gastrointestinal tract, introducing the risk of infections if not sterile.
• Osmolality : Osmolality affects the movement of fluids and electrolytes across cell
membranes. Solutions must be isotonic to prevent osmotic imbalances. Similar
osmolality to blood plasma. E.g.- 0.9% saline.
• Volume and Injection Site Capacity :Excessive volume at the injection site can
cause tissue irritation or systemic complications.
• Stability :The preparation must remain chemically and physically stable under
physiological conditions. Avoid precipitation upon administration

13. FORMULATION
CONSIDERATIONS
• Pyrogen-Free : Free from pyrogens (substances that induce fever). Use of pyrogen-
free water, removal of endotoxins through depyrogenation processes.
• Isotonicity : Should match the osmotic pressure of body fluids to avoid irritation or
damage to tissues. Adjusting agents - Sodium chloride, Dextrose and Mannitol.
• Buffering Agents : These are require to adjust the ph of the preparation to a
acceptable range. E.g.- Citrates, Acetates and Phosphates.
• Solubility : Ensure the drug is soluble in the selected vehicle. For this we use co-
solvents (e.g., ethanol, propylene glycol).
• Vehicles: It help in the delivery of the drug to its target location. There are two types
of vehicles Aqueous vehicle ( WFI, Saline or dextrose sol. ) and non-aqueous vehicles
(Vegetable oils, synthetic oils)

14. • Antimicrobial Preservatives : Used in multi-dose preparations to inhibit microbial
growth. E.g.- Benzyl alcohol, phenol, methylparaben.
• Antioxidants : Prevent oxidation of active ingredients. E.g.- Ascorbic acid, sodium
bisulfite.
• Stabilizers : Protect drugs from degradation due to light, heat, or moisture. E.g.-
EDTA (chelating agent), albumin.
• Surfactants : Enhance solubility and stability of emulsions or suspensions. E.g.-
Tween 20, Tween 80.
• Compatibility :Prevent undesirable interactions between the drug and formulation
components. Ensure the formulation does not interact with the container materials.
• Viscosity : Formulation must be easy to inject without causing pain or requiring
excessive force. Polymers are added to modify viscosity when needed.
• Packaging : Containers – Ampoules, Vials, Pre-filled syringes, Large infusion bags
or bottles are used. Rubber stoppers and Aluminum caps are used to maintain
sterility and prevent contamination.

15. MANUFACTURING PROCESS
Following steps are involved in the processing of parenteral preparations –
• Cleaning of containers, closures & equipments:
Thoroughly cleaned with detergents with tap water - distilled water - finally rinsed
with water for injection.
▫Rubber closures are washed with 0.5% sodium pyrophosphate in water.
• Collection of materials:
All raw material of preparation should be collected from the warehouse after accurate
weighing.
▫Water for injection should be pyrogens free.
• Preparation of parenteral products: The parenteral preparation must be prepared in
aseptic conditions.
▫The ingredients are accurately weighed separately and dissolved in the vehicle
as per the method of preparation to be followed.

16. •Filtration: The parenteral preparation must be filtered by bacteria proof filter such as
filter candle, membrane filter.
•Filling the preparation in final container: The filling operation is carried out under
strict aseptic precautions.
•Sealing the container: Sealing should be done immediate after filling in aseptic
environment.
•Sterilization: For thermostable substances the parenteral products are sterilized by
autoclaving method at different temperature & pressure.
▫Heat sensitive or moisture sensitive material are sterilized by exposure to ethylene
oxide or propylene oxide gas.
•Evaluation of the parenteral preparation: Sterility testing, Clarity test, Leakage
test, Pyrogen testing and Assay.

17. Sterilization

18. •Storage:
Store in a sterile, airtight, tamper-proof container.
•Labeling :
The term labeling designates all labels and other written, printed or graphic
matter on in any package or wrapper in which it is enclosed.
Materials used in labeling
• Paper
• Foil
• fabric

19. EVALUATION
1. Sterility testing
2. Leaker testing
3. Particulate Matter Testing
4. Pyrogen testing
i. Rabbit test
ii. LAL test

20. 1. Sterility Testing
Objective: To ensure that parenteral preparations are free from viable microorganisms,
which could cause infections if administered.
• Direct Inoculation Method:
The sample is directly introduced into two types of culture media:
o Fluid Thioglycollate Medium (FTM): Supports the growth of anaerobic and
aerobic bacteria.
o Soybean Casein Digest Medium (SCDM): Supports the growth of fungi and
aerobic bacteria.
These samples are incubated for 14 days at 30-35 C and 20-25 C respectively
⁰ ⁰
Observations: Any turbidity or microbial growth in the media is indicative of
contamination.

21. •Membrane Filtration Method:
o Suitable for large volumes or products with antimicrobial properties.
o The sample is filtered through a sterile 0.45 μm or 0.22 μm membrane.
o The membrane is then placed in FTM and SCDM and incubated as per the
conditions mentioned above.
o Observations: Growth indicates contamination.
•Acceptance Criteria:
No microbial growth should be observed in either medium after the incubation period.

22. 2.Leaker Test
• Leaker test for ampoules is intended to detect incompletely sealed ampoules
so that they can be discarded in order to maintain sterile condition of the
medicines.
• Tip seals are more likely to be incompletely closed than pull seals.
• Open capillaries or cracks at the point of seal result in LEAKERS.
• The leaker test is performed by immersing the ampoules in a dye solution,
such as 1% Methylene blue, and applying at least 25 inches of vaccum for a
minimum of 15 mins.

23. •Detection of leaker is prominent when ampoules are immersed in a bath of dye
during autoclaving as this has advantage of accomplishing both leaker detection
and sterilization in one operation.
•Another means of testing for leakers is a high frequency spark test system
which detect presence of pinholes in ampoules.
•Bottles and vials are not subjected to such a vacuum test because of the
flexibility of the rubber closure.

24. 3. Particulate Matter Testing
• Particulate Matter (PM) refers to the tiny particles suspended in the drug
sol , which can include dust, dirt, soot, smoke, and liquid droplets. These
particles are categorized by their size, commonly referred to as PM10
and PM2.5.
• Particulate Matter Testing is performed to ensure parenteral preparations
are free from visible and sub-visible particles that could harm patients.
• It is examined by :-
• Visual Inspection
• Sub-Visible Particle Testing

25. •Visual Inspection:
• Each container is examined under a strong light source against a black-and-
white background.
• Any visible particulate matter or turbidity is considered a failure.
•Sub-Visible Particle Testing:
These have particles which are not visible to the eye and are on the smaller scale.
Performed using:
• Light Obscuration Method: Measures the scattering of light by particles.
• Microscopic Method: Particles are counted using a calibrated microscope.
•Limits:
Small Volume Parenterals:
• Particles ≥10 µm: Not more than 6,000 per container.
• Particles ≥25 µm: Not more than 600 per container.
Large Volume Parenterals:
• Particles ≥10 µm: Not more than 25 per mL.
• Particles ≥25 µm: Not more than 3 per mL.

26. 1. Light Obscuration Particle Count Test:
Principle: Detects and counts particles in a liquid preparation by measuring the
reduction in light intensity as particles pass through a detection zone.
Procedure:
• The sample is degassed to remove air bubbles.
• The preparation is passed through a light obscuration instrument.
• Counts are recorded for particles ≥10 µm and ≥25 µm in size.
2. Microscopic Particle Count Test:
Principle: Particulate matter is counted visually using a microscope after filtration
through a membrane.
Procedure:
• The sample is filtered through a membrane filter.
• The filter is examined under a microscope for particles ≥10 µm and ≥25 µm.

27. 4. Pyrogen Testing
• The Pyrogen Test is a quality control test conducted to detect the presence of
pyrogens, which are fever-inducing substances, in pharmaceutical products,
particularly parenteral preparations. These pyrogens are typically derived from
microbial contamination (e.g., endotoxins from Gram-negative bacteria) and can
cause febrile reactions when introduced into the bloodstream.
• Purpose of the Pyrogen Test
The test ensures that parenteral products are free from harmful levels of pyrogens,
safeguarding patient safety and meeting regulatory standards for pharmaceutical
quality. It is particularly critical for injectable drugs, intravenous fluids, and medical
devices that come into direct contact with the bloodstream.

28. 1. Rabbit Pyrogen Test
•Principle: This test evaluates the febrile response of rabbits after intravenous
administration of the test sample.
Procedure: Selection of Rabbits:
• Healthy rabbits weighing not less than 1.5 kg.
• Acclimatize rabbits in controlled conditions (ambient temperature: 20–25°C) for
1–3 days before testing.
• Measure and record baseline rectal temperatures over three days to ensure
stability.
Preparation of Test Sample:
• The test sample (product) should be free of any visible particulates.
• Administer the product intravenously at a dose of 10 mL/kg of body weight.
Testing:
• Record the baseline rectal temperatures of the rabbits before administration.
• Administer the test solution via the ear vein.
• Measure the rectal temperature of each rabbit at 1, 2, and 3 hours after injection.
Interpretation:
• Calculate the temperature rise for each rabbit.

29. 2. Limulus Amoebocyte Lysate (LAL) Test
Principle:This test detects bacterial endotoxins using a reagent prepared from the blood cells of the
horseshoe crab (Limulus polyphemus). Endotoxins catalyze the formation of a gel or cause turbidity
or color change in the presence of LAL. It is faster and does not require live animal for testing.
Types of LAL Tests: Gel Clot Method:
• Formation of a firm gel indicates the presence of endotoxins.
• Conduct serial dilutions of the sample to determine the endotoxin concentration.
Turbidimetric Method:
• Measures the increase in turbidity caused by the reaction of endotoxins with LAL.
• The optical density is measured spectrophotometrically.
Chromogenic Method:
• Measures the color change resulting from the reaction of endotoxins with a chromogenic
substrate in the LAL reagent.
• The intensity of the color change is proportional to the endotoxin concentration.
Procedure for LAL Test:
Prepare the test sample and control solutions.
Add the LAL reagent to the sample in a controlled environment.
Incubate at 37°C for 60 minutes (gel clot) or measure turbidity/color change spectrophotometrically