PARENTERALS LARGE AND SMALL VOLUME PARENTAL PPT Download

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1

PARENTERALS
LARGE AND SMALL
VOLUME PARENTAL

PRESENTED BY :
JOGINDER PRESENTED TO :
1ST SEMESTER, M.PHARMA DR. YASMIN SULTANA
(PHARMACEUTICS).
School Of Pharmaceutical School Of Pharmaceutical
Education and Research, Education and Research,
JAMIA HAMDARD J AMIA HAMDARD

 

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CONTENT
 Introduction
 Routes of administration
 Advantages & disadvantages
 Small Volume Parental (SVP)
 Large Volume Parental (LVPs) and it’s type
 Processing of parenterals
 Formulation of parenteral
 Packaging & Sterilization
 Comparision between SVP & LVP
 Evaluation of parenterals
 References

 

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INTRODUCTION
Parental refers injectable route of administration.
 It is derived from GREEK word Para (outside) and

Enteron (intestine).
 It defined as sterile drug, solution or suspension that is

packaged in a manner for suitable administration by
hypodermic injection either in the prepared form or
after addition of a suitable solvent or suspending agent.
These are the preparations which are given other than

oral routes.

 

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Parenteral products are injected through the skin or
mucous membranes into the internal body
compartments.
Based on volume they are classified into two types :

1 ) Small volume parental ,
2 ) Large volume parental .

 

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ROUTES OF ADMINISTRATION :
 € ROUTES OF ADMINISTRATION

Three primary routes of
parenteral administration are
commonly employed :€
1) Subcutaneous
2) Intramuscular €
3) Intravenous €

 Other routes :
Intra-arterial,Intraarticular,
Intraspinal , Intracerebral,
Intracardial , Intrapleural

,Intraocular, Intrapritoneal.

 

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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.

 

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DISADVANTAGES :
€ Pain on injection.
Difficult to reverse an administered drug’s 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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Small Volume Parental(SVP)

According to USP “ an injection that is packaged in
containers labeled as containing 100 ml or less” is called
as SVP.

 

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€ All the sterile products packaged in vials, ampoules,
syringes, bottles or any other container that is 100ml or
less fall under the class of SVP.
Ophthalmic products packaged in squeezable plastic

containers, although topically applied to the eye rather
than administered by injection, also fall under the
classification of Small Volume Injections (SVI) as long as
the container size is 100ml or less.
 SVP aqueous solutions can be administered by

intravenous route because of local irritation.

 

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 Small volume parenteral products can be formulated and
packaged in several ways and include a wide variety of
products like :
 Pharmaceutical products.
 Biological products.
 Diagnostic agents.
 Allergenic extracts.
 Radiopharmaceutical products.
 Dental products.
 Genetically engineered or biotechnology products.
 Liposome and lipid products.

 

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Large Volume Parenterals (LVPs)

A single-dose injection that is intended for intravenous
use and is packaged in containers labeled as containing
more than 100 ml.
Packaged in glass bottles or in large volume flexible

containers.
 May contain greater than 100 ml to greater than 1 or 2 L.
 Sterile and pyrogen-Free.
Essentially free of particulate matter.
No anti-microbial agents.

 

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Types of Large Volume Parental

Electrolytes
Carbohydrates
Nutritional Solutions

– Proteins
– Lipid Emulsions

Peritoneal Dialysis
 Irrigating Solutions

 

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COMPARISION
PARAMETERS SVP LVP

Volume <= 100 ml 101 – 1000ml

Route IV , IM , SC IV

Dosage Unit Single or Multiple Multiple

Preservative Used Not used

Buffer Used Not used

Isotonicity Not essential Must

Pyrogenicity Not essential Must

Formulations Solution. Solution,
Emulsion. O/W emulsion.
Suspension.

Uses As therapeutic agent, As nutrition, Detoxification,
As diagnostic agent. Aid during surgery.

 

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FORMULATION OF PARENTERAL

1) Therapeutic Agents
2) Vehicles
 Water
 Aqueous vehicles
 Non-aqueous vehicles
3) Added substances (Additives)
 Antimicrobials

 Protectants
 Antioxidants

 Solubilizing Agents
 Buffers

 Stabilizers
 Bulking agents

 Tonicity-adjusting agents
 Chelating Agents

 

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1) Therapeutic Agents
Ex : Insulin , Antibiotics , Vaccine , Antipyretics ,
Analgesiics , Dextrose , Nacl , Electrolytes.

2) Vehicles : Water
1) 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.

 

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 Stored for less than 24hr at RT or for longer times at
specific temperatures. Should be meet USP pyrogen test
It may not contain any added substances. €
 Stored in chemically resistant tank.

2) 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 contain 0.9% benzyl alcohol that is used to dilute or

dissolve medications.

 

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3) Sterile Water for Injection USP (SWFI) :

 Sterile , nonpyrogenic , distilled water in a single dose
container for intravenous administration after addition of
a suitable solute.
 It may also be used as a dispensing container for diluent

use.
No antimicrobial or other substance has been added.
The pH is 5.5 (5.0 to 7.0).
 Sterile Water for Irrigation, Wash wounds, surgical

incisions, or body tissue.

 

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Aqueous vehicles
 These are primarily to effect solubility of drugs and

reduce hydrolysis.
Prepared by Distillation , ion exchange or reverse

osmosis.
Except purified water all are pyrogen free.

Non-aqueous vehicles
Fixed oils , Peanut oil , Cotton seed oil , Sesame oil,

Soybean oil, Ethyl oleate , Isopropyl myristate.

 

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PRETREATMENT OF WATER

The water for injection is most commonly used solvent.
Water for injection is the water prepared by reverse

osmosis or distillation and contains no added
substance.
The water must be adequately pretreated to ensure the

uniformity and to promote constant quality and high
efficiency.

 

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REVERSE OSMOSIS (RO)

This is define as a process for the separation of solutes
from the water by applying pressure on more
concentrated solution in contact with semi permeable
membrane to give less concentrated solution.
The solutes may be charged (ions) or essentially neutral

(organics).
Each is excluded or removed by different mechanisms.
Charged particles are repelled or excluded due to

interfacial tension at the water membrane interface.

 

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 Organics are excluded by sieve
mechanism so that size and molecular
weight are important attributes.
 The higher the size or molecular
weight of a substance, the most
efficiently it is excluded.
 Thus virus, bacteria, and pyrogen are
removed by reverse osmosis.
 The overall system primarily depends
on the composition of feed water and
the quality of the final water desired.

 

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DISTILLATION
 The action of purifying a liquid by a process of heating and cooling.
 The process of removal of impurities from the liquid by continuous

heating above 100 degrees and at atmospheric pressure cooling
simultaneously.

 This aids in killing the living microorganisms.
 Prior to distillation , water used as source for WFI should be done

with pretreatment.
 Perfect phase change would leave all the impurities behind producing

pure water vapor.
 After this the vapor is condensed to liquid water.
 It is maintained at pressure greater than the water of lower purity.

 

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The objective is to control the
number of organisms per unit
volume of water used for final rinses
of equipment and containers.
After distillation it is filtered and
stored in a chemical resistant
stainless steel tank at a cold
temperature around 5 0C or at an
elevated temperature between 65-
85 0C to inhibit the microbial
growth and pyrogen formation.

 

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3) Additives in Parenteral :
Antimicrobials :
 Required to prevent microorganism growth during storage.
 Phenylmercuric nitrate and Thiomersol 0.01% Benzethonium

chloride and benzalkonium chloride, Phenol or cresol 0.5% –
Chlorobutanol 0.5%

Antioxidants :
 Antioxidants function by preferentially with molecular oxygen and

minimizing or terminating the free radical auto-oxidation
reaction.

 eg – Reducing agents : sodium bisulfite, ascorbic acid, thiourea.
Blocking agents : ascorbic acid esters, butylated

hydroxytoluene (BHT), butylated hydroxyanisole (BHA) .
Synergistic : citric acid , tartaric acid, citraconic acid.

 

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Buffers
 Added to maintain pH Results in stability Effective range,

concentration, chemical effect
 e.g : Citrate and Acetate buffer, and Phosphate buffer

Citrates pH 2 – 6
Acetates pH 4 – 6

Phosphates pH 6 – 8

Bulking agents
For freeze dried preparation (solids) eg mannitol, lactose

sucrose, dextrose.

 

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Chelating Agents
 Release of heavy metals from the rubber closers etc can react with

the main medicament of the preparation, to prevent chelating
agents mainly trisodium or calcium disodium salt of ethylene
diamine tetra acetic acid (EDTA).

Solublizer, wetting agent or emulsifier :
Lecithin , Polysorbate 80(Tweens) , Sodium deoxy cholate

, Theophylline .

Stabilizers :
 Creatinine , Glycine , Sodium caprylate .

 

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Tonicity Modifiers :
Most important for intraspinal injections and intravenous

injection.
 In case of intraspinal injections, because the circulation of the

cerebrospinal fluid is slow and slight disturbance of osmotic
pressure quickly cause headache and vomiting.

 Its not essential for subcutaneous and intramuscular
injection.

 Isotonic solution does not cause hemolysis.
 Electrolytes : Nacl €
Non elecrolytes : Glucose,Mannitol,Glycerine €
 Ex. Of isotonic:Dextrose injection 5%&Nacl injection 0.9%
 Toncity can be measurement by: Freezing point depression ,

Hemolytic method using RBC.

 

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PROCESSING OF PARENTERALS

S.NO. STEPS

1. Cleaning of containers, closures and equipments

2. Collection of materials

3. Preparation of parenteral products

4. Filtration

5. Filling the preparation in final containers

6. Sealing the containers

7. Sterilization

8. Evaluation of parenteral preparation

9. Labeling and packaging

 

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PACKAGING :

 €Packaging materials : Glass, Plastic, Rubber €
 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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CONTAINERS
1. GLASS :
 Highly resistant Borosilicate glass,
 Treated soda lime glass,
 Regular soda lime glass,
 N.P (Non-parenteral) glass.

Type 4 is not used for parenteral packaging , other all are used for
parenteral packaging.

2. PLASTIC
 Plastic containers are used but they face following problems
 permeation , sorption , leaching , softening .

 

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3. RUBBER :

 To provide closure for multiple dose vials, IV fluid bottles,
plugs for disposable syringes and bulbs for ophthalmic
pipettes, rubber is the material of choice.

 Problems associated with rubber closures are
incompatibility,
chemical instability,
physical instability .

 

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CLOSURE :
Characteristics of Good Pharmaceutical rubbers
 Good ageing qualities
 Satisfactory hardness and elasticity
 Resistance to sterilization conditions
 Impermeable to moisture and air

Examples :
 Butyl Rubbers , Natural Rubbers , Neoprene Rubbers ,

Polyisoprene rubbers , Silicone Rubbers

 

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€ STERILIZATION :

 Steam sterilization €
Dry heat sterilization €
 Sterilization by filtration €
Gas sterilization €
 Sterilization by ionizing radiation

 

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EVALUATION OF PARENTERALS

The finished parenteral products are subjected to the
following tests , in order to maintain quality control :

1) Sterility test
2) Clarity test
3) Leakage test
4) Pyrogen test
5) Assay

 

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1) Sterility test
 It is a procedure carried out to detect and conform absence of any

viable form of microbes in or on pharmacopeia preparation or
product.
Method of sterility testing
a) METHOD 1 Membrane filtration method
b) METHOD 2 Direct inoculation method

Membrane filtration method ( METHOD 1) :
 Membrane filtration Appropriate for : (advantage)

I) Filterable aqueous preparations
II) Alcoholic preparations
III) Oily preparations
IV) Preparations miscible with or soluble in aqueous or oily
(solvents with no antimicrobial effect)

 

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 All steps of this procedure are performed aseptically in a Class 100
Laminar Flow Hood.

Membrane filter 0.45μ porosity

Filter the test solution

After filtration remove the filter

Cut the filter in to two halves

First halves (For Bacteria)
Second halves (For Fungi)

Transfer in 100ml culture media
Transfer in 100ml culture media

( Fluid Thioglycolate medium )
(Soyabeans Casein Digest medium)

Incubate at 30-350C for not less then
Incubate at 20-250C for not less then

7 days
14 days

Observe the growth in the media
Observe the growth in the media

 

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Direct inoculation method (METHOD) :

 Suitable for samples with small volumes.
Volume of the product is not more than 10% of the

volume of the medium.
 Suitable method for aqueous solutions, oily liquids,

ointments and creams.
Direct inoculation of the culture medium suitable

quantity of the preparation to be examined is transferred
directly into the appropriate culture medium & incubate
for not less than 14 days.

 

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2) Clarity Test
 Particulate matter is defined as unwanted mobile insoluble matter

other than gas bubble present in the product.
 If the particle size of foreign matter is larger than the size of RBC ,

it can block the blood vessel.
 The permit limits of particulate matter as per I.P. are follows.

Particle size in µm (equal to or large than) Maximum number of particles per ml

10 50

25 5

50 Nil

 

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3) Leakage Test
 The sealed ampoules are subjected to small cracks which occur

due to rapid temperature changes or due to mechanical shocks.

Filled and sealed ampoules

Dipped in 1% Methylene blue solution
Under negative pressure in vacuum chamber

Vacuum released colored solution enter into the ampoule

Defective sealing
 Vials and bottles are not suitable for this test because the sealing material

used is not rigid.

 

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4) Pyrogen Test
 Pyrogen = Pyro (Greek=Fire) + Gen (Greek = beginning)

 Fever producing , metabolic by-products of microbial growth and
death.

 Bacterial pyrogens are called ENDOTOXINS. Gram negative
bacteria produce more potent endotoxins than gram positive and
fungi.

 Endotoxins are heat stable lipopolysaccharides (LPS) present in
bacterial cell walls, not present in cell-free bacterial filtrates.

 

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Limulus Amebocyte Lysate (LAL) Test

 Limulus Amebocyte Lysate (LAL) Test another method for the
determination of pyrogenic endotoxins.

 In this method the test solution is combined with a cell lysate from
the ambeabocyte (Blood Cells) of horse shoe crab.

 Any endo toxin that might be present will be coagulated with
protien fraction of the ameabocytes and results in the formation of
a gel.

 This consider to be simple , rapid and of greater sensitivity that
the rabbit test.

 

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5) Assay

Assay is performed according to method given in the
monograph of that parental preperation in the
pharmacopoeia.

Assay is done to check the quantity of medicament
present in the parenteral preperation.

 

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