Parenteral products. Injections Sterile products intended for administration into the body tissues. Their formulation should consider all of the following.

Parenteral products

Injections

• Sterile products intended for administration into the body tissues.

• Their formulation should consider all of the following inter-related factors:

• Proposed route of administration• Volume of inj.• Vehicle of dissolving or suspending the drug• Osmotic pressure of solution• Use of preservatives• pH of the solution• Stability of the medication & methods of

sterilization

• Specific gravity of the injection• Properties of suspension for injection• Properties of emulsion for injection• Containers or closure of injection• Particulate contamination• Biopharmacy of injection

The biopharmacy of injections

• The route of adm. Affects the formulation and the biopharmaceutics of the preparation

Routes of adminstration

Intracutaneous/Intradermali.c.

• Inj into skin btw dermis and epidermis• Vol. (0.1-0.2 ml) small, due to• Poor vascularity which gives poor dispersion

of drug and leaves blisters at site of injection• Used mainly for diagnostic tests.

Subcutaneous/Hypodermic s.c.

• Inj. In subcutaneous tissue• Vol. ≤1 ml.• Not for aqueous suspensions or oily

suspensions and fluids (may cause pain & irritation at inj site)

Intramuscular

• Inj. In muscle tissue• Vol. not greater than 2 ml & do not

exceed 4 ml• Used for aqueous & oily suspensions.

Intravascular

• Intraarterial (into arteries) vasodilator drugs in the treatment of vasospasm

and thrombolytic drugs for treatment of embolism

• Intavenous (into veins)• Most common median basilic vein• Vol. less than 1ml to excess of 500 ml• Small vol. for rapid effect/ large vol. to replace

body fluids

• This route ensures rapid body dispersion • o/w can be admistered by this route if the

globule size is controlled

Intracardiac

• Used for emergencies• Cardiac stimulants adrenaline/ isoprenaline• Given directly into the heart muscle or

ventricles

intraspinal

• Intrathecal/ subarachnoid i.t.• Inj. into subarachnoid space contains CSF• Used for spinal anasthesias, antibiotics

Intracisternal injection

• Inj into cisterna magna• Primarily for CSF removal • Can be used for antibiotics or investigation of

CSF

Peridural/ epidural

• Inj. into peridural space• This space extends throughout the full length

of the spinal column so inj. Can be made ( thoracic, lumbur, sacral)

• Used for spinal anasthesia

Intaarticular/ Intrabursal

• Intra articular: Inj. Into synovial fluid• Intrabursal inj. Into bursae (a small fluid-filled

sac lined by synovial membrane with an inner capillary layer of slimy fluid, It provides a cushion between bones and tendons and/or muscles around a joint )

• Most common subcromial bursa in shoulder, olecranon bursa in elbow.

• Solutions & suspensions may be administered

Ophthalmic route

• Subconjunctival route(underneath the conjuctiva, close to the eye but not into it)

• Intravitreous route (into vitreous chamber)• Intracameral route ( into anterior chamber)• Intaocular route ( into posterior segment of

globe)• Vol. never greater than 1 ml• Great care in choice of buffering agent

Others

• Intra ossicular ( into the bone marrow)• Intr cerebral • Intra peritoneal , dialysis• Intra pleural

Bioavailability of drug from injection

• Injections are used for rapid or localized activity.• Inj. Into bld →rapid spread before binding,

metabolism happens ( these ↓ conc.)• Intrathecal, intracisternal, intracardiac, iv routes

used for rapid onset of action compared to tablets that need disintegration, dissolution then absorption.

• Formulation, different site of administration → different biopharmacy of the drug

• pH of inj. Affect degree of ionization of the drug making it less or more to pass through membranes .

• Viscosity : ↑viscosity will slow the absorption from i.m.

• Solubility polymorphism affect solubility of drug (novobiocin, chloramphenicol)

• Suspensions: particle size affects the activity of the drug

• ↑ particle size of insulin →↓availabile surface area →↓ absorption ( SR effect)

• ↓particle size of procain Pec. G →↑ blood levels

Route of adm. Affects disposition & biopharmacy of the drug

• i.v route • Immediate & total access of the drug to body• Maximum plasma conc. Within minutes• Duration of action may be affected by dose

distribution, metabolism, excretion of drug, elimination usu. 1st order

• i.v. drips → constant blood levels

• i.m./s.c. can act as SR routes but this depends on dosage form

• Aq. Sol. → most rapidly absorbed into bld• Aq. Susp.→retarded release ( dissolution)• Oily susp. →further delay of absorption

( partitioning of drug from oil)• Viscosity, Drug conc, patient movement and

differences in choice of muscle influence absorption.• Generally s.c. give slower absorption (vascularity)

Formulation of injection

• The reference here is BP

Volume of injection

• Depend on -solubility of the medication -particular route• i.c. small to prevent blisters• i.v. Suitable for large volumes but must be

isotonic• i.v. vol. more than 15ml contain no bactericide

and should be free from pyrogens• Vol. should be convienient to adm.

The vehicle

• Pharmacologically inert• non-toxic (must be tested exhaustively)• compatible with bld• non-sensitizing• non-irritating.• Maintain solubility of AI• Chemically & physically stable• Unaffected by pH changes• Should not interfere with the therapeutic activity of the

inj.

• Water is the ideal vehicle for most inj. • Aq. Preparations are well tolerated by the

body & are safest & easiest to adm.• Water might not be ideal for all formulations• Hydrolysis of drugs →inert/ toxic byproducts• Poorly soluble/insoluble drugs →need for

cosolvent

• Propylene glycol for dimenhydrinate inj. BP• Benzyl benzoate & arachis oil for dimercaprol

inj. BP• Oily vehicles give depot effect over the aq

counterpart• Progesterone (poorly soluble) formulated in

ethyl oleate or fixed oils →depot release

• Propyliodone BP ( contrast media of x-ray exam. Of RT) present as:

• Aqueous suspension• oily suspension in arachis oil• Oily susp. Is prefered as it is less irritating

Disadvantages of oily injs.

• Maybe too viscous in cold weather to adm. w/o warming

• Often cause pain at site of inj• Will contaminate the syringe & needle making

them difficult to clean• Must be used only by i.m. route. If given i.v.

thrombosis

• Contrast media (iodised oil fluid inj. BP, propyliodone inj. BP) may be given by other routes → injected into internal cavities under investigation, lungs

• Very occasionally alcohol is used to dissolve the medicament but the solution must be diluted with an aq. Vehicle shortly before adm. To avoid pain & tissue damage

pyrogens

• A substance that induces fever• Endogenous, Exogenous• Pyrogenic molecules have high Mwt.• Substances that are pyrogenic may be

produced by many organisms including moulds , bacteria, yeasts

• Most potent endotoxins originating from CW of gram –ve bacteria

• Lipopolysaccharide (LPS) in CW of G-ve bacteria, in body binds to lipopolysaccharide binding protein (LBP)

• The LBP-LPS complex binds to CD14 receptor on macrophage →synthesis & release of various endogenous cytokines

Sources of pyrogens

• Solvent ( major source, esp. water for inj. )• Medication• Buffering or stabilizing substances• Apparatus used in manufacturing• Final container• Method of storage btw preparation &

sterilization

Physiological response to pyrogens

• Erythema at site of inj.• Pain in the legs & trunk• General discomfort• High temperature• The BP uses temp. as the basis to estimate

pyrogensPyrogenic→ fever producingApyrogenic

Pyrogen tests are applied to:

• All inj. Claimed to be apyrogenic→• Water for inj. BP• Single dose inj. Of vol greater than 15 ml• Powders which require reconstitution/

reconstituted inj.• i.v. infusions ( if they contain pyrogens → rapid

effect, could be fatal)

Water for injection BP

• Sterilized distilled water • free from pyrogens• Prepared from potable water• None of the methods of inj. Sterilization can

be relied upon to eliminate pyrogens as they are thermostable, water soluble, not affected by common bactericides

• Pyrogens are non-volatile• They can be removed from water by

distillation.• Ordinary distillation is not sufficent (pyrogens

may be carried over in the receiver, dissolved in the spray which is entrailed in the steam).

• So a trap is fitted to the distilling flask to stop this entrainment.

• Certain bacteria are able to multiply in distilled water.

• Inadequate protection from air & storage at temp. that favours bacterial growth may cause a rapid increase in bacterial count.

• Ideally distilled water for parenteral solutions should be sterilized immediately after collection from the still.

• The exception is when the water is used at once for making an inj. That requires sterilization.

• Distilled water may be used after a much longer storage provided it is maintained at a high temp. ( bacterial growth & pyrogen production will be preserved)

• BP gives Special warning for large vol. infusion fluids for their immediate sterilization.

• Another method of preparing water for inj. Is reverse osmosis (USP)

• Water for inj. BP sometimes be necessary to further improve its quality by removing dissolved gases.

• Ex. Barbiturates weakly acidic & only slightly soluble in water → adm. As more soluble sodium salts

• Amylobarbitone sodium ( solubility 1 in less than 1) dissolved in water containing CO2 →

precipitation of the amylobarbitone base(solubility 1 in 1500) rendering it dangerous & unsuitable for inj.

• Amylobarbitone Na (solubility 1 in less than 1)• Dissolved in water containing CO2 → precipitate

the free base amylobarbitone ( solubility 1 in 1500). (dangerous & insuitable for injection).

• Other injections requiring water free from CO2 • Aminophylline injection BP • Methohexitone injection BP • Sodium bicarbonate i.v infusion BP

• Thiopentone inj. BP does not need water for inj free from CO2 because the official substance is mixture of thiopentone and sodium carbonate which will keep salt in solution.

• CO2 can be removed from water for inj. BP by boiling the water for 10 min.

• The residual air at the top of the amp. Is replaced by nitrogen or other inert gases after packing, before sealing.

• This product replaces normal water for inj. In products containing medications that are sensitive to oxidation.

• Chlorpheniramine injection BP• Chlorpromazine injection BP• Phenylephrine injection BP• Promazine injection BP

Water miscible vehicles

• Sometimes the medication is not soluble in water, to increase the solubility toxic solvent can be added

• ethyl alcohol, glycerol, propylene glycol, liquid macrogols, benzyl benzoate)

• Ethyl alcohol (used only when other methods are impracticable)

• Due to its physiological activity, pain , tissue damage, unless administered with care

• Used in few preparations• Digoxin inj. BP, Ergotamine inj. BP, Phenytoin inj. BP.

Contain a low concentration to facilitate solution of the active.

• Melphalan inj. BP is a solution in a vehicle containing 95% ethyl alcohol but is diluted before use

• Propylene glycol is included in several preparations including Cotrimoxazole, Digoxin, Dimenhydrinate, Melarsoprol, Phenobarbitone, Phenytoin injections BP.

• Old Digoxin inj. BP contains 70% ethyl alcohol which had to be diluted with NaCl inj. BP & given i.v. by slow inj. To ensure rapid dilution with blood.

• Now it is 40% propylene glycol, 10% ethyl alcohol & water buffered to about pH 7 & does not require dilution before use.

• Phenobarbitone inj. BP was prepared by asptically dissolving sterile phenobarbitone sodium in water for inj. BP free from CO2 immediately before use

• Now solution in 90% propylene glycol which is stable enough for steriliztion to 98-100 and has satisfactory storage life.

• Propylene glycol is relatively non toxic( possibly it is rapidly metabolized & excreted)

• It causes sever pain & irritation on s.c. & i.m. inj. & preferably should not be given by these routes, unless anesthetic is included ( benzyl alcohol) e.g. dimenhydrinate inj

• Liquid macrogols have been recommended as prospective vehicle

• Care must be taken during their sterilization as formaldehyde can be generated

Water- immiscible vehicles

• 8 of the oily inj. Of BP are simple solutions• Ex. Deoxycortone acetate inj. ,

hydroxyprogesterone inj., oestradiol benzoate inj.

• Solvents are suitable fixed oils, suitable ester, or a mixture of both

• Suitable alcohols may be included in the solvents for Deoxycortone acetate, Osteradiol benzoate , progesterone injs. BP

• Fixed oils must not contain • mineral oils or soild parrafins (not metabolized

by the body, cause tissue reactions, even tumors)

• Free form rancidity (free fattr acids)• Free from irritation

Arachis oil

• Used in dimercaprol & propyliodone inj. BP• Disadvantage: thickening slowly on exposure

to air and becoming rancid• Alternatives: • sesame oil (most stable as it contains natural

substances that prevent rancidification)• Cotton seed oil/ maize oil• Sensitivity to these oils may cause problems

Esters

• Give less viscous preparations that are easier to inject, esp cold weather

• But a reduction in length of action of depot preparations has been found when ethyl oleate has been used instead of oil

• The maximum prolongation effect is obtained from the depot if it is spherical droplets and absorption is probably more rapid from less viscous ester because of their tendency to spread and offer a larger surface to the tissues fluid

• They must be free from peroxide since they are the intermediate in the auto-oxidative and rancidification of oils and fatty acids & they are undesirable in inj. Esp. when medication is susceptible to oxidation

• Ex. Calciferol inj. BP ( also it requires storage in amp. From which air has been replaced by inert gases)

Alcohol

• Alc. may be used in addition to oil if the solubility of drug in oil is not enough to obtain the desired concentration.

• Ethyl alcohol/ benzyl alcohol can be used in concentrations that are harmless and non-irritant by i.m

others

• Almound oil• Poppyseed oil• Isopropylmyristate• Polyethylene oleic triglycerides

Osmosis

• When a solvent passes through a semi permeable membrane from a dilute solution into a more concentrated one, with the result that the concentration become equalized.

• Osmotic pressure is the pressure responsible for the above phemonenon

• It is caused and varies with the solute

• If the solute is nonelectrolyte, its solution will contain only molecules, and the osmotic pressure of the solution will vary only with the concentration of the solute

• If the solute is electrolyte, its solution will contain ions, and the osmotic pressure will vary with the concentation & degree of dissociation of the solute

• ( greater no. of particles→ greater osmotic pressure

Iso-osmotic vs. isotonic

• The terms iso-osmotic & isotonic are not to be considered as equivalent

• If a cell is in contact with a solution that has the same osmotic pressure as the cell contents, there will be no net gain or loss of water by either solution provided the cell membrane is impermeable to all the solutes present

• As the volume of the cell contents remains unchanged , the tone or normal state of the cell is maintained, and the solution in contact with the cell may be considered not only as being iso-osmotic with the solution in the cell, but also as being isotonic with it.

• If one or more of the solutes in contact with the membrane can pass through it, the volume of the cell content will change, thus altering the tone of the cell

• In this case the solutions maybe iso-osmotic yet not to be isotonic

Preparation of isotonic solution

• Comparison of freezing point is used• The freezing point of blood, serum and

lacrimal fluid is -0.52• 1 g molecular weight of any nonelectrolyte

dissolved in 1000g water the freezing point depression is about 1.86

Example

• How many grams ofBoric acid Mwt. (61.8) are needed to make a solution in water isotonic

61.8→-1.86 X→ -0.52 x= -0.52*61.8/-1.86 x= 17.3 g in 1000 g of water

electrolyte

• Osmotic pressure depends more on the number than the kind of particle, substances that dissociates have a tonic effect that increases with the degree of dissociation

• The greater the dissociation, the smaller the quantity required to produce any given osmotic pressure

• The dissociation factor ( i ) • We may use the following values:• Substances that dissociate into 2 ions : 1.8• 3 ions : 2.6• 4 ions : 3.4• 5 ions : 4.2

Example

• How many grams of sodium cholride ( Mwt. 58.5) are needed to make water isotonic

58.5/1.8→-1.86X→ -0.52X= 9.09g in 1000g of water

• Hypotonic: solutions with lower osmotic pressure than the blood

• Hypertonic: solutions with higher osmotic pressure than the blood

• Both can be termed paratonic

• Very Hypotonic solution/ large vol. of less hypotonicity adm.→ RBC swelling & brust ( hemolysis)

• Which is irreversible & dangerous if large no. of cells is involved

•

• Hypertonic solutions may be adm. Without damage to RBCs (RBCs shrink but assume their normal shape when osmotic pressure returns to normal).

• Although isotonic solutions are preferred, hypertonic solutions are normally used since preparing isotonic solutions of many medications may require large vol. of water which would be difficult to adm.

• So hypertonic are inj i.v. slowly to ensure rapid dilution in bld. And minimal effect on RBCs.

• Certain injs. May irritate & damage the walls of veins. This maybe used intentionally (tmt. Of varicose veins)

• Sclerosing varicose veins

Intrathecal injections

• Isotonic• Inj of paratonic solution cause local

disturbances in osmotic pressure as CSF vol. is small, also a small inj. Will affect osmotic pressure causing headache and vomiting.

Intramuscular injections

• Aqueous solutions of medication intended to be absorbed quickly should be slightly hypertonic. (exoosmosis)

• Slow absorption or depot • Aq susp.(insoluble form of drug) or solution or

suspension in a hydrophobic vehicle.

Intracutaneous injections

• Isotonic• This route is used for diagnostical purposes

which is dependent on immune response so only the active should be the cause of inflammation.

• Paratonic solutions can irritate the skin

Subcutaneous injections

• Isotonic are preffered to reduce pain• Paratonics can be administered

Hydrogen ion concentration (pH)

• The pH is adjusted to a definite value or pH range

• Use of buffers to stabilize the pH is permitted• Reasons for pH adjustment include:

Increase the stability of the injection

• Unstable medicaments have their pH adjusted to the optimum for maximum stability

• This is important for inj. Which have to withstand heat sterilization or have a long shelf life.

• The utilization of an optimum pH is used to stabilize inj of antibiotics ( benzylpenicillin, tetracycline) vitamins ( cyanocobalamin)

Minimize pain , irritation & necrosis

• The optimum for stability may not prove a suitable formulation

• Very acid or alkaline solutions are very painful on injection & may cause irritation or necrosis of tissue esp. with s.c. or i.m routes

• i.v if given slowly are rapidly diluted & pH is neutalized by plasma buffers.

• i.t, intacisternal should be adjusted to btw pH 7-7.6, ideally 7.4 as non neutral solutions can cause aseptic memingitis.

• When acidic or basic substances are used in preparation of injection the pharmacopia ensures that no significant excess of these substances is present.

Provide unsatisfactory conditions for growth of microorganism

• Use can be made of low & high pH to prevent the growth of MO.

• Solutions of pH below 4 are bactiricidal to many MO & may not require additional protection against bacteria.

• This effect is less marked for moulds as they can tolerate acid pH

• Ethanolamine inj. BP does not require bactericide due to its high pH

Enhance physiological activity

• Sometimes maximum physiological activity is shown by neutral or alkaline solutions while maximum stability is found in acid media, the pH should be kept as high as physiologically possible with an acceptance level of stability.

Buffers

• No toxicity• Compatible with medication & other added

substances• Have high buffer capacity

• Change in the pH of the final product can be due to

• Decomposition of drug• Leaching of alkali from glass container• Extraction of acid or alkaline impurities from

rubber closure • So careful selection & preparation of

containers & closures

Suitable buffers include:

• Citric acid/ sodium phosphate ( digoxin)• Sodium acetate (insulin zinc suspension)• Sodium phosphate • Dipotassium hydrogen phosphate• Borates are too toxic to use in injections

Example

• Benzylpenicillin injection BP • Optimum range for the stability of penicillin solution

is 6-7• Hydrolysis occur in aq. Solutions → formation of

inactive benzylpenicilloic acid.• This results in ↓ in pH which further catalyses

hydrolysis • Leading to progressively greater acidity and more

rapid hydrolysis until the antibiotic has been destroyed

• Decomposition can be retarded by buffering the pH of the solution in range 6-7 with 4.5% w/v Na-citrate

• The life of the inj. Is increased from 7 days to 14 days if stored at 10⁰C

• The use of insoluble forms of drug to prolong action like :

• Protamine zinc insulin ( effect lasts 24-36 hr.) compared to plain insulin (6-8 hrs.)

• Because insulin protamine zinc is in a very insoluble complex from which it is only slowly made available to the body.

• This complex is most insoluble over narrow pH range (6.9-7.4) a phosphate buffer is used to prevent variations.

Specific gravity of the injcections

• Very important in spinal anasthesia • If the upper part of the pateints body is raised

by slopping the operating table• Solutions of lower s.g than the spinal fluid will

tend to rise on inj• Those with higher s.g will tend to sink• If patient is tilted head downwards, opposite

will occur

• Careful choice of s.g of the solution & the position of the patient so movement of the inj. Will be in the right direction.

• S.g of the CSF is not constant (average figure 1.0059 at 37⁰C)

• Isobaric: equal s.g• Hypobaric: lower s.g• Hyperbaric: higher s.g

Suspension for injection

• Good for:• Formulation of low solubility drugs• Increased stability of some medications• Effective depot release• Problem: • The drug must remain suspended for a time to

enable withdrawal of a uniform dose, esp. multiple-dose containers

Wettability

• Some substances( cortisone acetate, procaine pen.) are poorly soluble in water & poorly wetted by it.

• This is linked to particle size• Very fine particles are difficult to wet• So it is difficult to break up the clumps in any simple

aq. Susp.• The foam produced from shaking would take a long

time to disperse as it is stabilized by the film of unwettable powder at the liquid air interfaces

• To ensure satisfactory wetting of the solid it is necessary to reduce the interfacial energy btw it & the liquid

• This is achevied by adding a suitable wetting agent & non-ionic types are widely used

(polysorbates, Na sorbitan trioleate)

Sedimentation rate

• One of the difficulties in use of susp. Is quick sedimentation

• This is decreased by adding a hydrophilic colloid to increase the viscosity of the vehicle which holds the particles in suspension long enough for an accurate dose to be removed & at the same time helps to prevent the reformation of clumps

• A desirable property of a suitable colloid is rapid solution because suspensions have to be reconstituted just before use

• Ex. Carboxymethylcellulose, polyvinylpyrrolidone, gelatin, methylcellulose.

Claying

• A deflocculated suspension is often unsatisfactory because when small particles settle they produce a very tightly packed sediment that is hard to disperse this is said to have clayed.

• This can be avoided by reducing the amount of wetting agent, sufficient is added to take the powder into suspension but the quantity added is not enough to break down the smaller aggregates

• Partially deflocculated susp. Will settle more quickly but the sediment is loose & easy to disperse

• Procaine pen. Susp. • Very small quantity of Al trichloride produced

flocculated susp. Which was unsightly.• Partial flocculation using monosodium citrate

with small quantity of a protective colloid or sorbitol

Size & shape of particle

• The depot effect of a susp. Is influenced by both size & shape of the suspended particles.

• Larger particles produce a greater depot effect (take longer to be absorbed).

• But large crystals sediment quickly. Causing more pain on inj. & tend to block needle.

• Crystals which are isodiametric( cubic, insulin/platlet, procaine penicillin) are better than long acicular crystals since they can block needle .

• In certain cases, care must be taken to prepare crystals in stable structure

• Some are unstable & on storage in susp may either change into a more stable polymorphic form or show crystal growth becoming too large

Thixotropy

• A preparation in which particles are so highly flocculated (unpourable paste), by careful choice of the particle size & percentage of powder, these pastes can become thixotopic.

• →solid in the absence of shearing forces, & become fluid if tapped or shaken, & the original structure being resumed after a few minutes at rest

• The advantage that the particle remain in more or less permanent susp during storage & yet when required for use, the pastes are readily made fluid by tapping or shaking.

• The shearing forces on the inj. As it is pushed through the needle ensures that it is fluid when injected but the rapid resumption of the gel structure prevents excessive spreading in tissue & consequently a more compac depot is produced than with non-thixotropic susp

Preparation of aq. susp .

• 1. recrystallization of the drug followed by particle size reduction

• 2. sterilization of the drug• 3. Sterilization of the vehicle• 4. aseptic wetting of the powdered drug by the

vehicle• 5. Aseptic dispertion and milling of the susp• 6. Aseptic filling into the final steril container • sealing

Suspension in oily vehicle

• Oily preparation contain hydrophobic vehicle, insoluble drug → depot effect

• Aq. Preparations are preferred even they do not have a powerful depot effect

Addition of a gelling agent

• In sterile pen G procaine with Al stearate susp. USP, the drug is suspended in peanut or sesame oilthat has been gelled with 2% of Al stearate.

• Al stearate produces a molecular lattice structure that gives rigidity to the preparation & render it thixotropic

• Procaine pen G tend to clay if allowed to sediment rigid gel prevents this

Particle size

• Crystalline zinc insulin in aq susp → large particles give a greater depot effect

• Procaine pen G in oil containing Al stearate reduction of particle size gives increased prolongation

• Particles of procaine pen are coated with water repellent Al stearate & less easily reached by aq. Tissue fluids & absorption is delayed

• ↑ division of powder →greater its surface area→the greater the area of protective coating

Emulsions for injection

• Are thermodynamically unstable system that require stabilizers either surface active agents or finely divided particles.

• Ideally dispersed droplets are 0.5-1.0 µm in diameter, this corresponds to the size of the chylomicra

• Few globules are greater than 3 µm• Unstable emulsions are dangerous since their

storage may result in ↑ globule size due to coalescence → thrombosis if injected

• The emulsifers & stabilizers used should be non toxic

• Lecithin, polysorbate 80, gelatin, methylcellulose & serum albumin

• Phytomenadione inj BP, lecithin is used as emulsifying agent

i.v. therapy & emulsions

• i.v. used to correct deficiencies in the electrolytes & fluid balance, provide parenteral nutrition

• Solutions for i.v. infusions are clear & may contain ethanol, a.a, carbohydrates, vitamins

• Glucose metabolsim provide 14.3 kJ/g of energy

• Fat metabolism provide 37.7kJ/g

• Fat emulsions are used in TPN as a concentrated source of energy

• The aq. Phase is made isotonic by addition of glucose, sorbitol, glycerol

• The oily phase can consist of sesame, cod-liver, linseed, peanut, olive, more commonly cotton seed or soya bean oils

• Gelatin &/or cellulose derivatives may be included to increase viscosity of the emulsion so preventing coalescence.

• Emulsifiers like lecithins or fractionated egg yolk phospholipids together with surface active agents like Pluronic F68 or the polysorbates are used to stabilize emulsion

• Sterilization of the emulsion is a problem since the heat would coalesce the emulsion & filtration is impossible

• Rapid growth of MO in such emulsions is possible since there is no preservatives.

Colloidal dispersions & solubilized products

• Colloids can be prepared & used for inj.• Albumin, proteins, dextrans, & carbohydrates

polymers dissolve in water to form hydrophilic solutions.

• Certain inj. Are colloidal solutions, (Iron Dextran Injection BP,

• Iron Sorbitol Inj which is a complex of ferric ions, sorbitol, & citric acid stabilized with dextran & sorbitol

• Solubilized products can be used as inj.• Surfactant in solution form micelles whose

center will act as a solvent for lipid- solub;e materials

• By selective use of 1 or 2 surfactant & cosolvent it is possible to solubilize many drugs

Quality assurance of injections

Microbiological preservationthe use of bactericides in aqueous single dose injections

• Bactericides may be found in inj which are prepared either by heating with a bactericide or aseptic techniques

• They are allowed in aseptically produced products to supress the growth of MO inadvertently added during preparation

• Chlorocresol(0.2% w/v), phenylmercuric nitrate ( 0.002% w/v) , phenylmercuric acetate (0.002% w/v) are recommended by the BP as being suitable for heating with a bactericide

• The bactericide is included in the preparation at the conc. Recommended & the contents are maintained at 98-100 ⁰C for 30 min to effect sterilization

• Aseptic preparation of injections involving sterilization by membrane filtrationrequires high degree of skills to prevent accidental contamination

• The BP allows the addition of a suitable bactericide to the solution before filtration

• If the inj solution contain a bactericide it is important to remember that single dose inj will also contain the bactericide & cannot be used for intraoccular, intracardiac, intraspinal

The use of bactericide in multiple-dose container

• Multiple-dose containers contamination may be due to:

• Failure to sterilize the cap before withdrawing a dose

• Failure in sterilization of the needle or syringe• Injection of unsterile air or inrush of unsterile

as the needle is withdrawn

• The danger is in the rapidity in which they can multiply

• The last dose may contain millions of organism• The BP states:• Aqueous preparations supplied in containers for

use on more than one occasion contain suitable antimicrobia preservative in appropriate concentration except when the preparation has adequate antimicrobial properties.

• A multiple dose injection sterilized by the process of heating with bactericide should not require additional bactericide

• The bactericide used in multiple dose container destroy vegetative bacteria in a few hours at room temp but they are not usually capable of killing bacterial spores

• Number of contamination will remain small• Some bacteria & moulds have destructive action on

medication

Bactericide suitable for aqueous injections

• The desirable features of a suitable preservative for multipledose container

• Ability to prevent the growth & preferably to kill contaminating organisms

• Compatibility with medicament, even on long storage, should not interfere with the therapeutic efficacy of the product

• Low absorption rate into rubber• Absence of toxicity to the patient

• A broad spectrum of activity to include fungi, vegetative bacteria

• Activity over a wide pH range• It should be uninfluenced by the container• Stability in aqueous solution at high temp if

the inj is to be sterilized by moist heat sterilization

• The BP suggests :• o-cresol , chlorocersol, benzylalcohol,

phenylmercuric salts• The pharmaceutical Codex :• Phenol, chlorbutol, phenylmercuric acetate or

nitrate• This gives a choice that allows for

incompatibilities with medicament

• Phenol is not appreciably absorbed by rubber and may not always prove suitable

• pH may affect activity :• Phenol, o-crsol, chlorocesol are active up to a

pH of about 9• Chlorobutol is less active above pH of 5 ,

unstable above Ph 6• Phenylmercuric acetate is active only above pH

6

• Care has to be taken with solubility• Interactions of preservatives with containers

may include the leaching of hydroxyl ions, reducing the activity of phenol by increasing the pH

• Toxicity may involve hypersensitivity

• If other suitable alternative in particular formulation is needed it can be used but it should have a bactericidal activity at least equivalent to that of 0.5% phenol according to pharmaceutical codex

• The BP recommends that the no. of bacteria recovered per ml is reduced by a factor of not less than 10³ within 6 hrs of challenge & no organism is recovered from 1 ml at 24 hrs & thereafter

• In addition the no. of moulds & yeasts recovered per ml is reduced by a factor not less than 10² within 7 days of challenge & no increase thereafter

• Thiomersal 0.01-0.02 % is used in certain immunological preparations

• Benzyl alcohol 0.9%

• An additional preservative is unnessesary in multiple-dose container inj prepared by heating with a bactericide as they contain one

• No one is needed when the medication has bactericidal activity

Bactericides suitable for oily injections

• Oily preparation in multiple dose container• Phenol, cresol, chlorocresol• These bactericides may afford some

protection from contamination with vegitative micro-organism but are ineffective against sporing organisms

• MO are less likely to grow in anhydrous envir.

Limitations to the use of bactericides

• In large vol. i.v inj ( ˃ 15ml)→toxic dose• Not used in infusion fluids ( cannot be packed

in multi-dose container, or sterilized by heating with a bactericide)

• Not used in intracardiac, intra-arterial inj ( damage the affected tissue/organ)

• Not used i.t, intracisternal, peridural ( irritation, inflammation, aseptic meningitis)

• Injections fo i.t, intacisternal, peridural should be packed in single dose container, sealed by fusion of glass

• Ophtalmic route should not contain bactericides

Incompatibilities of common bactericides

• Phenol is not compatible with procaine penicillin, quinine HCL

• Cresol : carbacol, ergotamine• Phenylmercuric acetate: ascorbic acid ,

pethidine• Chlorocresol is less satisfactory, many

incompatabilities

• may be due to :Salting out of the bactericide by strong solutions of drug

• Insufficient purity / chlorocresol• Phenol & cresol have few incompatibilities &

are valuable for the majority of protein preparations ( immunological products)

Chemical stability of the medicamentadjustment of pH

• pH adjustment is a major method of stabilizing inj.

• Loss of activity is negligible provided the preparation is packed & stored correctly

Addition of a reducing agent or antioxidant

• Most popular reducing agents are sulphurous acid salts ( Na sulphite,Na metabisulphite , Na bisulphate)

• They are used to retard the oxidation of drugs that are readily oxidized in aq soln to form colored decomposition products

• The reducing action of dextrose may be used, carbacol inj BP

• Thiourea has been recommended as an antioxidant for ascorbic acid inj.

• Propylgallate is usu included in oily inj, ethyloleate to prevent rancidification

• i.t must not contain antioxidants• Morphine for i.t use is free from antioxidants

but it will degrade.

Replacement of air by inert gases

• In products sensitive to O2• Nitrogen is satisfactory

Use of sequestering agents

• Traces of heavymetals may catalyse destructive changes in drug ( breakdown, oxidation, degradation)

• These effects can be prevented by adding a sequestering agent that will form a soluble coordination compound with the metal in which the metal is held in a nonionizable form the will mostly suppress the catalytic activity of metal

• Ethylenediamine tetra-acetic acid (EDTA) is usually used as its salts

• If a sequestering agent is used to prevent metal-catalysed oxidation, they are usually more effective if a reducing agent is present

Inclusion of a specific stabilizer

• Sodium Bicarbonate Injection BP• Solutions of sodium bicarbonate when heated

form sodium carbonate & liberate carbon dioxide

• Carbonate may cause hemolysis & Ca precipitation

• To prevent decomposition the container should be thoroughly sealed to prevent gas loss during sterilization

• The inj should be saturated with CO2 before sterilization

• Precipitation of Ca / Mg carbonate may occur due to impurities in the bicarbonate or to the extraction of Ca/ Mg ions form the glass container so 0.01% disodium edetate is permissible to sequester the ions

Limitations in the use of additives

• It should not interfere with the activity of the drug

• Safe• Effective at low conc.• Stable to heat & storage• They should not be used unless there is value

of their use

Particulate contamination

• May arise from• Materials arising from the drug, vehicle,

added substances not filtered out prior to filling to final container

• Materials present in the final container which were not removed by rinsing prior to filling

• Materials falling by chance into the final container during filling process

• Such materials may include cellulose fibers, dust, cotton fibers, hair, dandruff, loose skin from human origin, microbial contamination

• Some filters may shed particles during use

• The container or closure may be source of particles either during storage or removal of doses prior to adm.

• Thus constituents of closures may deposit into the injection during sterilization

• So closures may be coated with a lacquer but this may also flake into medicament

• On withdrawal of a dose the penetration of the needle through the closure may result in coring or forcing rubber particles into inj.

• Inj may react with glass causing flaking• Physical forces required to open amp. May

cause glass spicules to be deposited in inj

• Particle contamination may cause inflammatory response, tissue growths possibly leading to neoplasms, antigenic reactions, occlusion of blood vessels leading to damage esp. in brain, kidney, liver & eyes