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FORMULATION OF PARENTERAL PRODUCTS

SUBMITTED BYJISNA SEBASTIANFIRST YEAR MPHARM

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PARENTERALSThe term derived from Greek word ‛Para’ outside &

‛Enterone’ intestine.

Parenterals are sterile solutions or suspension of drug in

aqueous or oily vehicle.

Parenteral drugs are administered directly in to the

veins, muscles or under the skin , or more specialized

tissues such as spinal cord.

Term parenteral used for any drug/fluid whose delivery

doesn’t utilize the alimentary canal for entering in to the

body tissues.

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General requirements for parenteral dosage forms

• Stability• Sterility• Free from pyrogens & toxins• Free from foreign particles• Isotonic• Chemical purity

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PARENTERAL ROUTES

The term parenteral literally means to avoid the

gut (gastrointestinal tract) and refers to any route of

administration outside of or beside the alimentary tract.

Thus, parenterals are injectable drugs that enter the body

directly and are not required to be absorbed in the

gastrointestinal tract before they show their effect.

Parenteral routes of administration usually have a more rapid

onset of action than other routes of administration.

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1. Intravenous

2. Intramuscular

3. Subcutaneous

4. intradermal

5. Intra-arterial

6. Intracardiac

7. Intrathecal

8. Intracisternal

9. Peridural

10.Intraarticular

11.Intracerebral

PARENTERAL ROUTES

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Intravenous

• The injection of a drug

directly into the patient's

veins, resulting in the

most rapid onset of action.

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IntradermalThe drug is injected into the top

few layers of the skin. Ideally,

the drug is placed within the

dermis. Used for diagnostic

agents.

SubcutaneousThe injection of the drug under

the skin into the fatty layer,

but not into the muscle.

Absorption of the drug is rapid.

Eg; insulin

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Intramuscular

Drugs are injected deeply into

muscle tissue. If the drug is in

aqueous (water) solution,

absorption is rapid. However, if

the drug is in an oily liquid or in

the form of a suspension, it can

prolong the release of the drug.

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ADVANTAGESUseful for patients who cannot take drugs orally

Rapid onset of action

Useful for emergency situations

Providing sustained drug delivery (implants, im depot inj)

Avoid first pass metabolism

Can inject drug directly in to a tissue (target drug delivery)

Useful for delivering fluids, electrolytes, or nutrients (TPN)

Can be done in hospitals, ambulatory infusion centers and

home health care centers

Complete bioavailability.

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DISADVANTAGESPain on injection

Difficult to reverse an administered drug’s effect.

Sensitivity or allergic reaction at the site of injection.

Requires strict control of sterility & non pyrogenicity than

other formulation.

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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CLASSIFICATION

1. Small volume parenterals (SVP)

2. Large volume parenterals (LVP)

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Small volume parenteralsUSP defn: An injection that is packed in containers labeled as

containing 100 ml or less.

Large volume parenteralsDefn: LVP are parenterals designed to provide :-

Fluid

Calories (dextrose solution )

Electrolytes

Combenation of these

Volume 101- 1000 ml

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DIFFERENCE BETWEEN SVP & LVPparameter SVP LVP

volume 100 ml or less 101-1000 ml

Routes IV, IM & SC IV- LVP & non IV- LVP

Dosage unit Single or multiple Single

preservative Used Not used

Buffers Used Not used

Formulation Soln, emulsion,suspension. Soln & o/w nutrient emulsion

Isotonicity Not essential must

Pyrogenicity Not essential must

use Therapeutic & diagnostic Nutrition,detoxification,And during surgery

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FORMULATIONAQUEOUS VEHICLE :

WATER FOR INJECTION (WFI) USP :

Highly purified water used as a vehicle for injective

preparations which will be subsequently sterilized.

USP requirement include not more than 10 parts per million

of total solids.

pH of 5.0 – 7.0 .

WFI may be prepared by either distillation or reverse osmosis.

Stored in chemically resistant tank.

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BACTERIOSTATIC WATER FOR INJECTION

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 30 ml or less.

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STERILE WATER FOR INJECTION

SWFI containing one or more suitable bacteriostatic agent.

multiple – dose containers not exceeding 30 ml.

They are permitted to contain higher levels of solid than

WFI because of possible leaching.

Used for washing wounds , surgical incisions, or body

tissues.

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WATER MISCIBLE VEHICLES

The number of solvents that are miscible with water has

been used as a portion of a vehicle.

Primarily to affect solubility of drugs and to reduce

hydrolysis.

Example:

Ethyl alcohol,

Liquid propelene glycol

Glycerine

Ethyl alcohol used in the case of cardiac glycoside.

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NON – AQUEOUS VEHICLES

Fixed oils (vegitable origin, liquid, and rancid

resistance ,unsaturated, free fatty acid content )

Peanut oil

Corn oil

Cotton seed oil (depo-testosterone)

Sesame oil

Soyabean oil

Ethyl oleate

Isopropyl myristate.

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OTHER ADDITIVESANTIBACTERIAL AGENTS

These are added in multiple dose containers.

To prevent microorganism growth

Limitted concenteration of agents are used.

Phenyl mercuric nitrate and thiomersol 0.01%.

Benzethonium chloride & benzalkonium chloride 0.01%.

Phenol & cresol 0.05%.

Chlorobutanol 0.05%.

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BUFFERS

Added to maintain pH.

To stabilize a solution from chemical degradation.

Citrate and acetate buffer.

Sodium benzoate and benzoic acid

Sodium tartarate and tartaric acid

Phosphate buffer.

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ANTIOXIDENT

To protect the formulation from oxidation

Two types

1. Reducing agents

Ascorbic acid

Sodium bisulfite 0.01%

Thiourea

2.Blocking agents

Tocopherol

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SURFACTANTS

Solubilise the active ingredient

Polyoxythylene sorbitan monooleate & Sorbitan

monooleate TONICITY AGENTS

Need isotonic solution to avoid destruction of red blood

cells, irritation, and tissue damage

More important for large volumes, rapidly administered,

and extravascular injections

Reduces the pain on injection

NaCl & KCl

Dextrose

Mannitol & Sorbitol Effect of different solutions on blood cells

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CHELATING AGENTS To remove trace elements that catalyse oxidative

degeneration

Ethelene diamine tetra acetic acid

CO-SOLVENT

Improve solubility

Prevent potential for hydrolysis

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BULKING AGENTS For freeze dried preparations(solids)

Mannitol

Lactose ,sucrose

Dextran .

SUSPENDING AGENTS

CMC,

Methyl cellulose, Gelatin

Sorbitol .

EMULSIFYING AGENTS

Lecithin

Polysorbate 80

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WATER FOR INJECTION (WFI):

A clear and colorless liquid; odorless.

Water for injections is pyrogen -free.

It contains no added substance.

Water for injections is obtained from potable or Purified water

by distillation in an apparatus.

The distillate is collected and stored in conditions designed to

prevent growth of microorganisms and to avoid any other

contamination.

 

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MANUFACTURING OF WFI :

• The source water usually must be pretreated by one or a

combination of following treatment:

• Chemical softening, filtration, deionization, carbon

absorption, or reverse osmosis purification.

• There are three types of distillation still to produce water for

injection.

1. Compression distillation

2. Multiple-effect still

3. Reverse osmosis

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• COMPRESSION DISTILLATION:

• Vapor compression still is primarily designed for the production of

large volumes of high purity distillate with low consumption of

energy and water.

• Vapor compression processes produce water 5 to 10 times more

cost effectively than multiple effect distillers.

• PROCEDURE:

• Step 1: In a Vapor Compression still, the boiling process begins

with both heating elements turned on. As the water in the boiling

chamber reaches near boiling temperatures, the compressor turns

on.

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• Step 2: In the compressor, the steam is pressurized, which

raises the steam's temperature before it is routed through a

special heat exchanger located inside the boiling chamber.

• Step 3: The pressurized steam gives off its heat to the tap

water inside the boiling chamber, causing this water to boil,

which creates more steam.

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• Step 4: While the pressurized steam is giving up its

latent heat, the steam will condense. One of the

heating elements will cycle on and off periodically as

needed.

• Step 5: At this stage, the condensed steam is

considered distilled water but is still very hot--only

slightly cooler than boiling temperature.

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COMPRESSION STILL

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MULTIPLE EFFECT STILL

• It is also designed to conserve energy and water usage.

• In principle, a series of single effect stills running at different

pressures.

• A series up to seven effect may be used, with the first effect

operated at a highest pressure and the last effect at

atmospheric pressure.

• The capacity of still can be increased by adding effects. The

quantity of distillate will also be affected by inlet steam

pressure

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PRODEDURE:

Steam from the external source is used in the first effect

to generate steam under pressure from feed water, it is

used as a power source for second effect.

The steam used to drive the second effect condenses

as it gives up its heat of vaporization and forms a

distillate.

The process continues until the last effect, when the

steam is at atmospheric pressure and must be

condensed in a heat exchanger.

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REVERSE OSMOSIS:

• The natural process of selective permeation of molecule

through a semi-permeable membrane separate two aqueous

solutions of different concentration is reversed.

• Pressure, usually between 200 to 400 psig, is applied to

overcome osmotic pressure and force pure water to

penetrate through the membrane.

• Membrane composed of cellulose esters or polyamides.

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•. It provide effective rejection of contaminant molecules in

raw water.

•Sodium chloride is most difficult to remove.

•Passage through two membranes in series is sometimes

used to increase the efficiency of removal of small

molecules.

• ex. Aqua chem , Finn-aqua, Meco , Milipore etc.

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STORAGE AND DISTRIBUTION

• Distillate is collected in holding tanks for subsequent use.

• USP permit the storage of WFI at room temp. maximum for

only about 24hr.

• When the water can not be used at 80º c , heat exchangers

must be installed to reduce the temperature at the point of use.

 

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LARGE VOLUME PARENTERALS

REQUIREMENTS

Sterile, non pyrogenic, free from particulate matter

Volume 101- 1000ml

Single dose unit

No preservative

Clear solution except fat emulsion

Isotonic, but hypertonic also administered in TPN

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TYPES OF LARGE VOLUME PARENTERALS

1.HYPER ALIMENTATION

SOLUTIONS

2. CARDIOLPAGIC SOLUTIONS

3. PERITONIAL DIALYSIS SOLUTION 4. IRRIGATING SOLUTIONS

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HYPERALIMENTATION SOLUTION

Admin. Of large amount of nutrients to patients who unable

to take food orally.

Formulation: mix. Of dextrose, amino acids , lipids,

electrolytes,& vitamines.

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TOTAL PARENTERAL NUTRITION

Def. :A method of feeding patients by infusing a mixture

of all necessary nutrients into the circulatory system, thus

bypassing the GIT. CONTENT SOURCES

1. calories Dextrose

2. Nitrogen Crystalline amino acids

3. Electrlyte Na , K, Cl , Po4,

4. Vitamines Water soluble & Fat soluble

5. Elements Traces of Zn, Cu, Mn, Cr

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2. CARDIOLPLEGIC SOLUTIONSAre LVP used in heart surgery to prevent injury to

myocardium during reperfusion, as well as to maintain

bloodless operating field.

Maintains the diastolic arrest.

Administerd in cold form.

Slightly alkaline to compensate metabolic acidosis,

Hypertonic

USE:

To minimize reperfusion injury resulting from tissue edema.

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3. PERITONEAL DIALYSIS SOLUTION

Infused continuously into abdominal cavity, bathing

peritonium & are then continously withdrawn.

USE

Removal of toxic substances from body.

To aid & accelerate excretion normal.

To treat acute renal insufficiency.

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4. IRRIGATING SOLUTIONS

To irrigate ,flush, & aid in cleaning body activities &

wounds.

Certain IV solution ( normal saline ) may be used as

irrigating solution , but solution designed as irrigating soln

should not be used parenterally.

Use: Treatment of serious wounds infused in to blood

stream.

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EXAMPLES OF LVP

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Small volume parenterals• Small volume intravenous injection is applied to an injection that is

packaged in containers labelled as containing 100 ml or less.

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1. Solution: 2. Suspension:

3. Emulsion: 4. Dry powders:

TYPES OF SVPs:

solutions • Typically used for delivering medications at a controlled infusion rate

• Most commonly solutions of 5% dextrose, normal saline, 45% normal

saline, or 5% dextrose with normal saline.

• Dextrose contributes glucose to meet energy needs and saline

contributes sodium, an electrolyte that maintains fluid balance and

cellular functions.

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SUSPENSION• They should be sterile, pyrogen free, stable, re‐

suspendable, syringeable, injectable, isotonic & non‐

irritating.

• They are usually administered by either subcutaneous

(S.C.) or intramuscular (I.M.) route.

• These suspensions usually contain between 0.5% and

5.0% solids & should have particle size less than 5

micrometer for I.M. or S.C. administration.

• Certain antibiotic preparations (For example procaine

Penicillin G) may contain up to 30% solids

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• Advantages of Parental suspension

• It is better for the therapeutic use of drugs that are

insoluble in convention solvents.

• In this dosage from there is increased resistance to

hydrolysis & oxidation as drug is present in the solid from.

• Formulation of controlled released drug is possible in this

dosage form.

• There is elimination of hepatic first pass effect.

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Injectable Emulsion-

• An emulsion is a heterogenous dispersion of one immiscible

liquid in another.

• This inherently unstable system is made possible through the use of

an emulsifying agent, which prevent coalescence of the dispersed

droplet.

• Parenteral emulsion are rare because it is necessary (and difficult)

to achieve stable droplet of less than 1 micron meter to prevent

emboli in blood vessels and it is not usually necessary to achieve an

emulsion for drug administration.

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Dry PowdersPurpose: To overcome the intrinsic instability of the drug, be

reconstitute before use.

• Production Method:

– Freeze-drying

–Aseptic crystallization and dry powder filling

– Spray-drying

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• Pharmaceutical product development by N K Jain.

• Theory and practice of industrial pharmacy byLachman and Leiberman.

• www. Google.com.

REFERENCE

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