SEMINAR ON

PARENTRALS

Presented by M.A. Zeeshan Ahmed M.Pharmacy I Semester, Pharmaceutics.

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CONTENTS
Introduction Routes of administration Advantages Disadvantages Preliminary stages Formulation Manufacture Filling Packaging Sealing Sterilization Quality control Conclusion References
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INTRODUCTION
DEFINITION According to USP :

an injection that is packaged in containers which are sterile and pyrogen

free in nature

A BRIEF ABOUT PARENTERALS : para: outside enteron: intestine Any drug or fluid whose delivery does not utilize the alimentary canal for entry into body tissues.

Parenteral products are injected through the skin or mucous membranes into the internal body compartments. These are the preparations which are given other than oral routes.

ROUTES OF ADMINISTRATION
Three primary routes of parenteral administration are commonly employed : Subcutaneous Intramuscular Intravenous Other routes : Intra arterial Intra athecal Intra articular Intra cardial Intra dermal Intra pleural Intra spinal Intra vascular
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 Parentrals are classified into two types. They are 1. Small Volume Parenterals (upto 100ml) Primary uses of SVP

Therapeutic injections Opthalmic products

Diagnostic agents
Allergenic extracts

2. Large Volume Parenterals (100-1000ml)

Clinical Utilization of LVP

Basic Nutrition Restoration of Electrolyte balance Fluid replacement Blood and blood products Drug carriers

ADVANTAGES
Quick onset of action Suitable for the drugs which are not administered by oral route Useful for unconscious or vomiting patients. Useful for patients who cannot take drugs orally Useful for emergency situations Duration of action can be prolonged by modifying formulation.

Can be done in hospitals, ambulatory infusion centers, and home health care
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DISADVANTAGES
Pain on injection. Difficult to reverse an administered drugs effects. Sensitivity or allergic reaction at the site of injection. Requires strict control of sterility & non pyrogenicity than other formulation. Only trained person is required Require specialized equipment, devices, and techniques to prepare and administer drugs. More expensive and costly to produce.
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PRELIMINARY STAGES
It includes : - Material management - Equipment and facility management - Personnel management - Documentation control

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FORMULATION
Aqueous vehicle : Water For Injection(WFI) USP :
Highly purified water used as a vehicle for injectable preparations which will be subsequently sterilized.

USP requirement include not more than 10 parts per million of total solids. pH of 5.0 to 7.0 WFI may prepared by either distillation or reverse osmosis. Stored for less than 24hr at RT or for longer times at specific temperatures. It may not contain any added substances. Stored in chemically resistant tank.

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Bacteriostatic Water for Injection (BWFI) :

This type of water used for making parenteral solutions prepared under aseptic conditions and not terminally sterilized. Need to meet USP sterility test. It can contain an added bacteriostatic agent when in containers of 30ml or less

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Sterile Water for Injection USP

SWFI containing one or more suitable bacteriostatic agents. Multiple-dose containers not exceeding 30 ml.

They are permitted to contain higher levels of than WFI because of the
possible leaching of glass container.

Wash wounds, surgical incisions, or body tissues.

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Water-miscible vehicles :
primarily to effect solubility of drugs and/or reduce hydrolysis

Non-aqueous vehicles :
Fixed oils (vegetable origin, liquid, and rancid resistance, unsaturated, free fatty acid content)
Peanut oil Corn oil Cotton seed oil (depo-testosterone) Sesame oil Soybean oil (source of fat in intralipid) Ethyl oleate Isopropyl myristate
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OTHER ADDITIVES
Antibacterial Agents

Required to prevent microorganism growth Limited concentration of agents - Phenylmercuric nitrate and Thiomersol 0.01% - Benzethonium chloride and benzalkonium chloride 0.01% - Phenol or cresol 0.5% - Chlorobutanol 0.5%

Buffers

Added to maintain pH Results in stability Effective range, concentration, chemical effect

Citrate and Acetate buffer Sodium benzoate and benzoic acid

Sodium titrate and tartaric acid

Phosphate buffer

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Tonicity Agents
Reduce pain of injection Can include buffers

Chelating agents
ethylenediamine tetraacetic acid

- Sodium chloride
- Potassium chloride - Dextrose - mannitol sorbitol CO2 (sodium bicarbonate injection)

Inert Gases
N2 (gentamycin sulfate injection)

Surfactants
polyoxyethylene sorbitan monooleate sorbitan monooleate

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MANUFACTURING

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Flow of Materials Through the Production Department

Ingredients Vehicles Solutes Compounding of Product Filtration Solution Filling Sealing Packaging Product storage

Processing Equipment
Container Components

Cleaning

Sterilization

Cleaning

Sterilization

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FILLING
1. Filling of liquids
A. Small volume parentrals Syringe based system Retraction device By gravity By pressure By vaccum

B. Large volume parentrals

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2. Filling of solids
Scoop method Machine (Auger) method Problems Stratification Electrostatic charges Air pockets Clumping

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Types of Filling Equipment

Mechanism of filling Types of product filled
solutions, suspensions emulsions and solutions ,, Rotary chemical pump Powders Time or pressure type Auger ,, Vacuum Pressure displacement ,, vials, bottles, plastic mini bags. ,,

types of package
vial, ampoules, plastic containers, bottles syringe cartridges, plastic mini bags

Piston type (Cozzoli) Liquid products such as

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PACKAGING
Glass containers :
Type Description
Highly resistant I Borosilicate Treated Soda Lime glass Soda lime glass Powdered Glass

Type of Test

General Use
Buffered and unbuffered aqueous solutions All other uses Buffered aqueous solutions pH<7.0, Dry powders, Oleaginous solutions

II

Water Attack

III

Powdered Glass

Dry powders, Oleaginous solutions

Not for Parenterals. For tablets, oral solutions and suspensions, ointments and external liquids

NP

General purpose Soda lime

Powdered Glass

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Plastic containers :
Thermoplastic
Polyethylene (Polyethene)High Density Polyethene Polyvinyl chloride (PVC) Poly methyl methacrylate Polystyrene Polypropylene Polyamides Polycarbonates

Closures :
Pharmaceutical rubbers
Butyl Rubbers Natural Rubbers

Thermosetting
Phenol Formaldehyde Urea Formaldehyde Melamine Formaldehyde

Neoprene Rubbers
Polyisoprene rubbers Silicone Rubbers

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PREFILLED SYRINGES :
Administration is more convenient for healthcare professionals and end
users.

Reduction of medication errors, better dose accuracy. Better use of controlled drugs such as narcotics. easy storage and disposal.

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SEALING
Sealing Ampoules
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

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Sealing of Bottles, Cartridges and Vials

Primary seal consisting of a tight rubber or plastic closure and secondary

seal that holds the primary seal in place.

Secondary seals are usually aluminum caps that are crimped on to a

thread less container.

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STERILIZATION
Dry heat sterilization Steam sterilization Sterilization by filtration Gas sterilization Sterilization by ionizing radiation

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QUALITY CONTROL
Sterility testing

Pyrogen test Clarity test

Leakage test
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1. STERILITY TESTING
A . Membrane filtration

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B. Direct inoculation of culture media

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2. PYROGEN TEST
A. Invivo test (Rabbit test)
Pyrogenic - means producing fever

Pyrogens - fever inducing substances

Endotoxins Produced mostly by gram-negative bacteria

Endotoxin - complex of pyrogenic lipopolysaccharide, a protein and inert lipid.

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The result of pyrogen test

No.of Rabbits
3 rabbits If above not passes 3+5 = 8 rabbits

Individual Tempt. Temperature rise Result rise (c) in group (c)

0.6 0.6 1.4 3.7 Passes Passes

If above test not passes perform the test again If above test not passes, the sample is said to be pyrogenic and the test fails

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B. Invitro test (LAL)

. Limulus polyphemus = horseshoe crab

Limulus - genera of crab

Amebocyte - crab blood cell from which active component is derived

The name of the test is also Limulus amebocyte lysate (LAL) test

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Mechanism of LAL
The test is based on the primitive blood-clotting mechanism of the horse shoecrab enzymes located with the crab's amebocyte blood cells + endotoxins (pyrogens)

incubated at 37c
initiation of an enzymatic coagulation

proteinaceous gel (with in 60 mins)

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Commercially derived LAL reagents

Lysate - component is obtained by separating amebocytes from the plasma and then lysing them. The hearts of mature crabs are punctured and bled to collect the circulating amebocyte blood cells. Since amebocytes act as activators of the coagulation mechanism in the crab, an antiaggregating agent must be added to inhibit aggregation. N-Ethylmaleimade is the most commonly used anti- aggregant. LAL test is the combinationof 0.1 ml test sample with 0.1 ml LAL reagent. After 1 hour incubation at 37C, the mixture is analyzed for the presence of a gel clot.

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3. CLARITY TEST

Unwanted mobile insoluble matter other than gas bubbles present in the given product.

It may be dangerous when the particle size is larger than R.B.C. & may block the blood vessel.
It can be done by the following methods.

A. Visual method B. Light scattering & Light absorption C. Light blockage method D. Coulter current method
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4. Leakage Test
A. Dye test (Ampoules)
Immersing the ampoules in a dye solution 1% metylene blue solution The vacuum on the tank is then released as rapidly as possible to put maximum stress on weak seals. Defective ampoules will contain blue solution.

B. Spark tester probe (Vials & Bottles)

Water hammer sound When the space is evacuated then it releases blue spark

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CONCLUSION
A wide variety of devices and new methods of drug delivery employed. Each has its advantage and disadvantages, which have to be carefully considered by the therapist. Parenteral dosage forms differ from all other drug dosage forms because they are injected directly into body tissues through primary protective systems of human body the skin and mucous membranes. They must be free of contaminating microorganism, harmful substances, free of pyrogenic contamination, free of particulate matter. In coming future we can expect much more advance technology in utilizing parenteral products for safety desirable effects in human being.

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REFERENCES
Theory and practice of Industrial pharmacy. Lieberman, Herbert A. Vol.1.Lachman, Third edition

Pharmaceutical Dosage Forms. Avis, Kenneth E. Vol. 2: Parenteral Medications

Pharmaceutical Dosage Forms. Avis, Kenneth E Vol. 3 : Parenteral Medications Pharmaceutical packaging technology. D A Deam , E R Evans, I H Hall

Modern Pharmaceutics. Gilbert S. Banker, Christopher T. Rhodes. Fourth Edition.

www.pharmaceuticalonline.com

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