Small Volume Parenteral

Presented by:Ajit Kumar JhaASU20140101000241st Sem. M. Pharma.(Pharmaceutics)School of PharmacyApeejay stya university

Parenteral

Parenteral refers injectable route of

administration.

It derived from Greek words Para (Outside) and

enteron (Intestine).

So it is a route of administration other than the

alimentary canal. This route of administration

bypasses the alimentary canal.

PRIMARY PARENTERAL ROUTESRoutes Usual volume

(mL) Needle commonly used

Formulationconstraints

Types of medication administered

SVP

Sub cutaneous 0.5-2 5/8 in. ,23 gauge

Need to be isotonic Insulin, vaccines

Intra muscular 0.5-2 1.5 in. ,23 gauge

Can be solutions, emulsions, oils or suspensionsIsotonic preferably

Nearly all drug classes

Intra venous 1-100 Vein puncture1.5 in. , 20-22 gauge

Solutions, emulsions and liposomes

Nearly all drug classes

LVP 101 and larger(infusion unit)

Venoclysis 1.5 in. ,18-19 gauge

Solutions and some emulsions

Nearly all drug classes

S. No. ADVANTAGES DISVANTAGES

1. Quick onset Wrong dose or over dose can be fatal

2. Vomiting and unconscious patients can take

Pain at site

3. Prolonged action by modified formulation( Depot)

Trained person required

4. Nutritive fluids (glucose,electrolytes) can be given

Expensive

5. Drugs with poor absorption or instability from GIT

NECESSITY OF ASEPTIC CONDITIONS IN PRODUCTION, COMPOUNDING AND ADMINISTRATION

Small Volume Parenteral

• According to USP : “ an injection that is packaged in containers labelled as containing 100 ml or less”

INTRODUCTION :• 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.

• 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. Small volume parenteral products can be formulated and packaged in several ways and include a wide variety of products like :

• Pharmaceutical products, Biological products, Allergenic extracts, Radiopharmaceutical products, Genetically engineered or biotechnology products, Liposome and lipid products.

• An injection is a preparation intended for parenteral administration and/or for constituting or diluting a parenteral article prior to administration

• Types of preparations :-

Drug injection

Drug for injection

Drug injectable emulsion

Drug injectable suspension

Drug for injectable suspension

Contd…….

• Definition:- According to the USP 24/ NF 19 “As those preparations intended for injection through the skin or other external boundary tissue, rather than through the alimentary canal”

• so that the active substance they contain are administered using gravity or force directly into a blood vessel,organ,tissue or lesion.

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, others all are used for parenteral packaging.

Contd…….

2. Plastic:

Plastic containers are used but they face following problems

• Permeation

• Sorption

• Leaching

• Softening

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

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

SYSTEM

COMPONE

NT

Preparatio

n

Area

Storage

Area

Personnel

Policies

and

Procedures

Admixture

system

PROCESSING OFPARENTERALS

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

Formulation of parenteral products• In the preparation of parenteral products, the following substances

are added to make a stable preparation:

The active drug

Vehicles Aqueous vehicle (e.g. water for injection, water for injection free from CO2

)

Non-aqueous vehicle (e.g. Ethyl alcohol, propylene glycol, almond oil)

Adjuvants Solubilizing agents (e.g. Tweens & polysorbates)

Stabilizers & antioxidants (e.g. thiourea, ascorbic acid, tocopherol)

Buffering agents (e.g. citric acid, sodium citrate)

Antibacterial agents (e.g. benzyl alcohol, metacresol, phenol)

Chelating agents (e.g. EDTA)

Suspending, emulsifying & wetting agents (e.g. MC, CMC)

Tonicity factor (e.g. sodium chloride, dextrose)

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

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.

Eg. propylene glycol or in combination with ethanol and polyethylene glycol.

Ingredients or added substances• Antimicrobial preservatives :

• Maintain the stability of the product during storage.

• Phenylmercuric nitrate and Thimerosal 0.001% , Benzethonium chloride 0.01%, Benzyl alcohol 0.5- 10.0%, Phenol or cresol 0.5%, chlorobutanol 0.5%.

• Buffers :

• Added to maintain pH Results in stability of drug against hydrolytic degradation or enhance the solubility of drug in solution.

• Common buffers used in SVPs

pH Buffer system Conc. %

3.5-5.7 Acetic acid-acetate 0.22

2.5-6.0 Citric acid-citrate 0.5

6.0-8.2 Phosphoric acid- 0.8-2

phosphate

8.2-10.2 Glutamic acid- 1-2

glutamate

Antioxidants :

Antioxidants function by preferentially with molecular oxygen and minimizing or terminating the free radical auto-oxidation reaction.

eg. Reducing agents: Ascorbic acid 0.02-0.1%, Sodium Bisulfite 0.1-0.15%, Thiourea 0.005%

Blocking agents: Ascorbic acid esters 0.01-0.015%, Tocopherols 0.05-0.075%

• Tonicity adjusters :

• Electrolytes: Nacl

• Non electrolytes: Glucose, Mannitol, Glycerine

• Eg. Of isotonic: Dextrose injection 5% & Nacl injection 0.9%

• Some solutions are iso-osmotic but not isotonic this is because the physiology of the cell membranes must be considered.

• For eg. the cell membrane of the RBC is not semi-permeable to all drugs it allows ammonium chloride, alcohol, boric acid, glycerin, propylene glycol, and urea to diffuse freely.

• In the eye the cell membrane is semi permeable to boric acid and a 2% solution is an isotonic ophthalmic solution.

• But even though a 2% solution of boric acid is an isotonic with the eye and is iso-osmotic, it is not isotonic with blood since boric acid can freely diffuse through the RBC– and it may cause HEMOLYSIS.

• Tonicity can be measurement by: osmometer

• Other ingredients :

• Bulking agents – for freeze dried preparations(solids) eg mannitol, lactose sucrose, dextrose.

• Suspending agents – Carboxy methyl cellulose, sorbitol.

• Emulsifying agents – lecithin, polysorbate 80

• Ophthalmic ointments bases – petrolatum.

Production 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

Contd…….Clean-up area:

It is not aseptic area. All the parenteral products must be free from foreign particles &

microorganism. Clean-up area should be withstand moisture, dust & detergent. This area should be kept clean so that contaminants may not be carried

out into aseptic area.

Preparation area: In this area the ingredients of the parenteral preparation are mixed &

preparation is made for filling operation. It is not essentially aseptic area but strict precautions are required to

prevent any contamination from outside.

Contd…….

Aseptic area: The parenteral preparations are filtered, filled into final

container & sealed should be in aseptic area.

The entry of personnel into aseptic area should be limited &

through an air lock.

Ceiling, wall & floor of that area should be sealed & painted.

The air in the aseptic area should be free from fibers, dust and

microorganism.

The High efficiency particulate air filters (HEPA) is used for air.

UV lamps are fitted in order to maintain sterility.

Contd…….

Quarantine area: After filling, sealing & sterilization the parenteral

product are held up in quarantine area. Randomly samples were kept foe evaluation. The batch or product pass the evaluation tests are

transfer in to finishing or packaging area.

Finishing & packaging area: Parenteral products are properly labelled and packed. Properly packing is essential to provide protection

against physical damage. The labelled container should be packed in cardboard

or plastic container. Ampoules should be packed in partitioned boxes

EVALUATION OF PARENTERAL PREPARATIONS

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

• A) sterility test

• B)clarity test

• C)leakage test

• D)pyrogen test

• E)assay

A) 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.

1) Method of sterility testing

i ) METHOD 1 Membrane filtration method

ii) METHOD 2 Direct inoculation method

Membrane filtration method (METHOD 1):

Membrane filtration Appropriate for : (advantage)

• Filterable aqueous preparations

• Alcoholic preparations

• Oily preparations

• Preparations miscible with or soluble in aqueous or oily

(solvents with no antimicrobial effect)

All steps of this procedure are performed aseptically in a

Class 100 Laminar Flow Hood

Composition of culture medium for sterility testing

Fluid Thioglycollate

Soybean- casein digest

L- cystine 0.5gm -

Sodium chloride 2.5gm 5.0gm

Dextrose 5.0/5.5gm 2.3/2.5gm

Pancreatic digest of casein 15.0gm 17.0gm

Papaic digest of soya bean - 3.0gm

Dibasic potassium phosphate - 2.5gm

Granular agar (moisture<15%) 0.75gm -

Yeast extract (water soluble) 5.0gm -

Sodium thioglycollate or thioglycolic acid

0.5gm or0.3ml

-

Resazurin (0.10%w/v fresh solution)

1.0ml -

Purified water 1000ml 1000ml

Components Culture medium

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 100 ml culture media(Fluid Thioglycollate medium)

Incubate at 30-350 C for not less then 7 days

Transfer in 100 ml culture media(Soyabeans-Casein Digest medium)

Incubate at 20-250 C for not less then 14 days

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

Direct inoculation method (METHOD 2):

Suitable for samples with small volumes

volume of the product is not more than 10% ofthe volume of the medium

suitable method for aqueous solutions, oilyliquids, ointments and creams

Direct inoculation of the culture medium suitablequantity of the preparation to be examined istransferred directly into the appropriate culturemedium & incubate for not less than 14 days.

B)clarity test

• Particulate matter is defined as unwanted mobile insolublematter other than gas bubble present in the product.

• If the particle size of foreign matter is larger than the sizeof R.B.C.. It can block the blood vessel.

• The permit limits of particulate matter as per I.P. arefollows:

Methods for monitoring particulate matter contamination:

1) Visual method

2) Coulter counter method

3) Filtration method

4) Light blockage method

C)leakage test

• The sealed ampoules are subjected to small cracks which occur due to rapid temperature changes or due to mechanical shocks.

Filled & sealed ampoules

Dipped in 1% Methylene blue solutionUnder negative pressure in vacuum chamber

Vacuum released colored solution enter into the ampoule

Defective sealing

Vials & bottles are not suitable for this test because the sealing material used is not rigid

D)pyrogen test

Pyrogen = “Pyro” (Greek = Fire) + “gen” (Greek= beginning).

Fever producing, metabolic by-products ofmicrobial growth and death.

Bacterial pyrogens are called “Endotoxins”.Gram negative bacteria produce more potentendotoxins than gram + bacteria and fungi.

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

Method Dissolve the subs being examined in, or dilute it with a pyrogen free saline

solution

Warm the liquid being examined to approx. 38.5o C temp before injection

The volume of injection is NLT 0.5ml/kg & NMT 10ml/kg of body weight

Withhold water during test

Clinical thermometer is inserted into the rectum of rabbit to record bodytemp

2 normal reading of rectal temp are should be taken prior to the testinjection at an interval of half an hr & its mean is calculated- initial temp

The solution under test is injected through an ear vein

Record the temp of each rabbit in an interval of 30 min for 3 hrs

The difference between initial temp & maximum temp is recorded- takenas response

Limulus amebocyte lysate [LAL] test

• Limulus amebocyte lysate [LAL] test another methodfor the determination of pyrogenic endotoxins

• In this method the test solution is combined with acell lysate from the ameabocyte [blood cells] of horseshoe crab

• Any endo toxin that might be present will becoagulated with protien fraction of the ameabocytesand results in the formation of a gel

• This consider to be simple,rapid and of greatersensitivity that the rabbit test

E)assay

• Assay is performed according to method given Inthe monograph of that parental preperation inthe pharmacopoeia

• Assay is done to check the quantity ofmedicament present in the parenteralpreperation

References

• Lachman/Lieberman’s “The Theory and Practice Of Industrial Pharmacy” Fourth Edition 2013, Edited by: Roop K Khar, SP Vyas, Farhan J Ahmad, Gaurav K Jain, CBS Publishers and Distributors Pvt Ltd, New Delhi.

• Doornbos C and Hann P. Optimization Techniques in Formulation and Processing. In Encyclopedia of Pharmaceutical Technology. Swarbrick J and Boylan JC, Eds., Vol. II, Marcel Dekker, New York. 199

• Modern Pharmaceutics Fourth Edition, Revised and Expanded, Edited By G.S.Banker & C.T.Rhodes, Marcel Dekker pg387-389.

• The Science & practice of Pharmacy, By Remington, Vol-01, 21st Edition, Lippincott Publication, pg-838-840.

Thank You……..