PARENTERAL FORMULATION

ERT 430 – PHARMACEUTICAL PROCESS ENGINEERING

OUTLINE

• Introduction

• Parenteral Product Requirement

• Parenteral Product Formulation:

– Solution– Solution

– Emulsion

– Suspension

• Evaluation of Parenteral Product

Introduction

Parenteral refers to injectable route of administration.

It is derived from Greek words Para (Outside) and

enteron (Intestine).enteron (Intestine).

So it is a route of administration other than the oral

route. This route of administration bypasses the

alimentary canal

• Necessities of Parenteral preparations: – Sterility (must)

– Pyrogen (must)

– Free from particulate matter (must)

– Clarity (must)

– Stability (must)

– Isotonicity (should)– Isotonicity (should)

– Solvents or vehicles used must meet special purity and other standards.

– Restrictions on buffers, stabilizers, antimicrobial preservative. Do not use coloring agents.

– Must be prepared under aseptic conditions.

– Specific and high quality packaging.

PARENTERAL PRODUCTS REQUIREMENTPARENTERAL PRODUCTS REQUIREMENT

• All products must be sterile.

• All products must be free from pyrogenic (endotoxin)

contamination.contamination.

• Injectable solutions must be free from visible particulate

matter. This includes reconstituted sterile powders.

• Products should be isotonic, although strictness of isotonicity

depends on the route of administration.

PARENTERAL PRODUCTS

• Solutions

• Emulsions

• Suspension (If the drug is insoluble, or poorly

soluble in a suitable solvent)soluble in a suitable solvent)

SOLUTION

• Most of injectable product are solutions

• Preparation:

– Dissolving drug and any excipients

– Adjusting pH

– Sterile filter (for heat sensitive) through 0.22μm – Sterile filter (for heat sensitive) through 0.22μm

membrane filter to achieve sterility & remove particulate

matter.

• Most solutions have a viscosity and surface tension similar to

water, athough streptomycin sulfate injection and ascorbic

acid injection are quite viscous.

SOLUTION

• Formulation

– Choice of solvent: water is the most widely used (eg: water for injection, prepared by RO or distillation)

– Other formulation additives

• Buffers• Buffers

• Isotonicity modifiers (to avoid pain & irritation): eg: dextrose, sodium chloride

• Density modifier (rarely necessary except when formulating spinal anaesthetics: to precisely control the area to be anaesthetized.)

• Reducing agents & antioxidants: eg: sodium metabisulphite, butylated hydroxyanisole

EMULSION

• Emulsion is a dispersion of one immiscible liquid in another.

• Using emulsifying agent: prevents coalescence of the dispersed droplets

2 types• 2 types

– Oil-in-water (o/w): Oil droplets are dispersed throughout the aqueous phase (usually given intramascularly)

– Water-in-oil (w/o): water is dispersed throughout the oil (usually given subcutaneously)

EMULSION

• An increasing popular class of IV emulsions is lipid emulsions.

• Fat is transported in the bloodstream as small droplets called chylomicra.

• Chylomicra are 0.5 to 1.0 μm spheres consisting of a central core of triglycerides and an outer layer of phospholipids.core of triglycerides and an outer layer of phospholipids.

• This emulsion yield triglycerides that provides essential fatty acids and calories during total parenteral nutrition of patients who are unable to absorb nutrients through GI tract.

• Glycerol is commonly added to make product isotonic.

• IV lipid emulsions are usually administered in combination with dextrose and amino acids.

EMULSION

2. FORMULATION:

severely restricted through a very limited

selection of stabilizers and emulsifiers.

Emulsion Ingredients:

A) Oils : The oils most commonly used are Long Chain Triglycerides

(LCTs) from vegetable sources (soybean or sunflower oil)

B) Emulsifiers: Natural and synthetic emulsifier are

a) Natural emulsifier- eg. lecithins.

b) Synthetic emulsifier- eg. Spans and Tweens.

C) Aqueous phase:

a) Water for injection is aqueous phase for parenteral emulsion.

b) Various substances have been added to the aqueous phase to

adjust osmolarity, pH.26/08/2013 12

D) Tonicity modifier :- Glycerol, sorbitol, xylitol are added in aqueous

phase.

E) Antioxidants :- α-tocopherol, ascorbic acid may be added in aq. Phase

to prevent peroxidation of unsaturated fatty acids.

F) Preservatives :- p-hydroxy benzoic acid (methyl and butyl derivatives)

can be dissolved in the aqueous phase.

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1) The emulsifier, and anypreservatives are usuallydissolved or dispersed in

2) The phospholipids,antioxidants, and anylipophilic drugs to beincorporated are usually

3) Both phases are thenheated to 70-85 o C withagitation.

Emulsion Manufacture:

A) Formulation Preparation:

26/08/2013 14

dissolved or dispersed inthe aqueous phase.

incorporated are usuallydissolved or dispersed inthe oil phase.

agitation.

4) The coarse emulsion isthen formed by vigorousstirring or mixing.

5) Final pH of formulationis adjusted.

B) Homogenization and particle size reduction: Can be

done by ultrasonic homogenizers,

C) Filtration: Membrane filter is used for final filtration to

remove larger particles.

D) Sterilization: For large-volume (l00 to 1000 ml.) injectable fat

emulsions, sterilization is achieved by autoclaving.

26/08/2013 15

Stability of parentral emulsions:

1) Stability of the formulation: Influenced by processing conditions,

autoclaving, storage conditions, excessive shaking, or the addition of

electrolytes or drugs.

2) Physical stability: Indicated by2) Physical stability: Indicated by

a) Particle size changes.

b) Flocculation.

c) Creaming, coalescence.

d) Extreme temperature fluctuation such as freezing can result in an

increased oil droplet size, leading to aggregation, coalescence, and

ultimate separation. 16

Physical instability

3) Chemical Stability: Indicated by

a) Oxidation.

b) Hydrolysis.

c) Change in pH.

4) Microbiological Stability: For bacterial and fungal growth.

� Precaution should be taken to prevent microbial contamination

during processing and maintain sterility.

26/08/2013 18

SUSPENSION

• Parentral suspensions are dispersed, heterogeneous systems containing insoluble

drug particles which, are to be resuspended in either aqueous or oil vehicles

before administering to a patient.

• They administered by either subcutaneous (S.C.) or intramuscular (I.M.) route.

• For example procaine Penicillin G.

• One of the most difficult to formulate: requires a delicate balance of variables to

formulate a product that is easily resuspended and can be ejected through an 18-

to 21 gauge needle through its shelf life

(To achieve these properties, it is necessary to select and carefully maintain the particle size and rheological properties, as well as the manufacturing steps that control the wettability and surface tension)

2) Syringeability &

3) Particle size should be small &

uniform.

4) Re‐suspension of

particles occur easily.

5) Dispersed particles do not settle rapidly

after shaking6) Cake formation not occur during its shelf

life.

7) Maintain its stability and elegance during its shelf life

‐

Ideal characteristics of suspension

1) Sterility during its storage & use.

2) Syringeability & injectability of a

suspension are closely related to viscosity &

particle characteristics.

8) Isotonic & non‐irritating

9) Contain 0.5% to 5.0% solids & particle size less

than 5 micrometer.

26/08/2013 20

Advantages of parenteralsuspension

1) Better for drugs that are insolublein convention solvents.

2) Increased resistance to hydrolysis

& oxidation as drug is present in thesolid from.solid from.

3) Formulation of controlled releaseddrug is possible

4) Elimination of hepatic first passeffect.

26/08/2013 21

Disadvantages

1) Stabilization of suspensions

for the period between

manufacture & use present a

number of problems. e.g. solids

gradually settle & may cake,

causing difficulty in

redispersion prior to use.

2) Maintenance of

physical stability is

very difficult in this

dosage form.5) Difficulty in

formulation: selecting the Disadvantages

of parenteral

suspension

dosage form.

4) Difficulty in manufacturing:

Special facilities required to maintain

aseptic condition for manufacturing

processes such as : crystallization,

particle size reduction, wetting,

sterilization

formulation: selecting the

ingredients, like

suspending agent,

viscosity inducing agent,

wetting agent, stabilizers

and preservative.

3) Non‐‐‐‐uniformity of

dose at the time of

administration.

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Formulation development:

� Suspension ingredients: Parenteral suspension contain both

active ingredient(s) and excipients.

� Excipients used in the parenteral preparations must be:

o Physically and chemically compatible with active ingredient.

o Nonpyrogenic, nontoxic, nonhaemolytic and nonirritating.

o Must not interfere with the therapeutic effect of the active

ingredient.

o Must maintain stability during sterilization and during the shelf

life

o Effective at low concentration.26/08/2013 23

Typical excipients used in parenteral suspensions:

1) Flocculating/suspending agents (to prevent caking )

2) Wetting agent

3) Solvents

4) Preservatives

5) Antioxidants.

6) Chelating agents.

7) Buffering agents.

8) Tonicity agents.

1) Flocculating/suspending agents:

a) Surfactants: e.g. Lecithin, Polysorbate 20, Polysorbate 40, Polysorbate

80,Pluronic F-68.26/08/2013 24

b) Hydrophilic colloids: e.g. Sodium CMC, Acacia, Gelatin, MC, PVP.

c) Electrolytes: e.g. Potassium/sodium chloride, Potassium/sodium citrate,

Potassium/sodium acetate.

2) Wetting agent: They reduce the contact angle between the surface of 2) Wetting agent: They reduce the contact angle between the surface of

the particle and the wetting liquid.

� Useful when hydrophobic powders are suspended in aqueous

systems.

e.g. Nonaqueous solvents (glycerin, alcohol, and propylene glycol).

Non ionic surfactant. (polysorbate 80, Polysorbate 20,Polysorbate 40).26/08/2013 25

3) Solvents: May be aqueous or non aqueous.

Water for injection is preferred aq. solvent system.

� Non aqueous solvent may be:

i. Water miscible ( Ethanol, Glycerin, Propylene glycol, N-(β

hydroxyethyl)-lactamide.

ii. Water immiscible includes fixed oils like Sesame oil, Peanut

oil, Castor oil, almond oil, sunflower oil, iodinated poppy

seed oil.

26/08/2013 26

4) Preservatives:

� Benzyl alcohol (0.9% to 1.5%), Methylparaben (0.18% to 0.2%),

Propylparaben (0.02%), Benzalkonium chloride (0.01 % to 0.02%), and

Thimersal (0.001 % to 0.01 %).

5) Antioxidants:

a) water soluble: Ascorbic acid- 0.02-0.1%, Sodium bisulfite- 0.1-0.15%,a) water soluble: Ascorbic acid- 0.02-0.1%, Sodium bisulfite- 0.1-0.15%,

Sodium metabisulfite- 0.1-0.15 %, Sodium formaldehyde sulfoxylate-

0.1-0.15%, Thiourea- 0.005%

b) Oil soluble: Ascorbic acid esters-0.01-0.15, BHT-0.005-0.02%,

Tochopherol- 0.05-0.075%.

26/08/2013 27

SUSPENSION

• 2 basic methods of preparation:

i) Sterile vehicle and powder are combine aseptically

Eg: procaine penicillin, an aqueous vehicle containing the soluble

components (such as lecithin, sodium citrate, providone &

polyoxythylene sorbitan monooleate) is filtered through a 0.22 μm

membrane filter, heat sterilized, and transferred into presterilizedmembrane filter, heat sterilized, and transferred into presterilized

mixing-filling tank. The sterile antibiotic powder, which has previously

been produced by freeze drying, sterile crystalization or spray-drying,

is aseptically added to the sterile solution while mixing. After all tests

have been completed on the bulk formulation, it is aseptically filled.

SUSPENSION

Previously sterilized &

milled active

ingredient(s)

Vehicle & Excipients

Sterilizing filter

(i.e. 0.22 micron)Sterile

receiving

vessel

Mixed/ milled

Final suspension

Aseptically disperse

active ingredient(s)

Aseptic filling

1. Aseptically combining sterile powder and vehicle26/08/2013

SUSPENSION

• 2 basic methods of preparation:ii) Sterile solutions are combined and the crystals formed in

situ.

Eg: testosterone suspension.

The vehicle is prepared and sterile-filtered. The testosterone is dissolved separately in acetone and sterile-filtered. The is dissolved separately in acetone and sterile-filtered. The testosterone-acetone solution is aseptically added to the sterile vehicle, causing the testosterone to crystallize. The resulting suspension is then diluted with sterile vehicle, mixed, the crystals allowed to settle, and the supernatant solution is siphoned off. This procedure is repeated several times until all the acetone has been removed. The suspension is then brought to volume and filled in the normal manner.

Active ingredient(s) in

solution (organic

solvent

Vehicle and

necessary

Excipients

Sterilizing filter

(i.e. 0.22 micron)

Counter

solventSterilizing filter

(i.e. 0.22 micron)

Sterilizing filter

(i.e. 0.22 micron)

Mill/ Mix

Remove organic

solvent

2. In situ crystal formation by combining sterile solutions.26/08/2013

EVALUATION OF PARENTERAL

PREPARATIONS

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

A) sterility testA) 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.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 :

– Filterable aqueous preparations

– Alcoholic preparations

– Oily 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

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 7 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% of

the volume of the medium

�suitable method for aqueous solutions, oily�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.

Observation and results

Culture media is examined during and after at the end of incubation. The

following observations are possible:

1) No evidence of growth Pass the test for sterility.

2) There is evidence of growth Re-testing is performed same no. of

sample, volume & media as in original test No evidence of growthsample, volume & media as in original test No evidence of growth

Pass the test for sterility.

3) There is evidence of growth isolate & identify the organism.

Re-testing is performed with twice no. of sample if:

No evidence of growth Pass the test for sterility.

B)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 R.B.V (red blood cell), it

can block the blood vessel.

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

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 solution

Under negative pressure in vacuum chamberUnder 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�Bacterial pyrogens are called “Endotoxins”. Gramnegative bacteria produce more potentendotoxins than gram + bacteria and fungi.

� Endotoxins are heat stable lipopolysaccharides(LPS) present in bacterial cell walls, not present incell-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 beforeinjection

� The volume of injection is NLT 0.5ml/kg & NMT 10ml/kg of bodyweight

� Withhold water during test

� Clinical thermometer is inserted into the rectum of rabbit to� Clinical thermometer is inserted into the rectum of rabbit torecord body temp

� 2 normal reading of rectal temp are should be taken prior to thetest injection 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 isrecorded- taken as response

Interpretation of results

Limulus amebocyte lysate [LAL] test

• Limulus amebocyte lysate [LAL] test anothermethod for the determination of pyrogenicendotoxins

• In this method the test solution is combined witha cell lysate from the ameabocyte [blood celels]a cell lysate from the ameabocyte [blood celels]of horse shoe crab

• Any endo toxin that might be present will becoagulated with protien fraction of theameabocytes and 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

In the monograph of that parental preperation

in the pharmacopoeia

• Assay is done to check the quantity of• Assay is done to check the quantity of

medicament present in the parenteral

preperation

Thank You……..