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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

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Parenteral products

Parenteral products


Injections
Injections

  • Sterile products intended for administration into the body tissues.

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


Parenteral products

  • 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


Parenteral products

  • 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 biopharmacy of injections

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


Routes of adminstration
Routes of adminstration


Intracutaneous intradermal i c
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
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
Intramuscular

  • Inj. In muscle tissue

  • Vol. not greater than 2 ml & do not exceed 4 ml

  • Used for aqueous & oily suspensions.


Intravascular
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


Parenteral products


Intracardiac
Intracardiac

  • Used for emergencies

  • Cardiac stimulants adrenaline/ isoprenaline

  • Given directly into the heart muscle or ventricles


Intraspinal
intraspinal

  • Intrathecal/ subarachnoid i.t.

  • Inj. into subarachnoid space contains CSF

  • Used for spinal anasthesias, antibiotics


Intracisternal injection
Intracisternal injection

  • Inj into cisterna magna

  • Primarily for CSF removal

  • Can be used for antibiotics or investigation of CSF


Peridural epidural
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
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
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
Others

  • Intra ossicular ( into the bone marrow)

  • Intr cerebral

  • Intra peritoneal , dialysis

  • Intra pleural


Bioavailability of drug from injection
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


Parenteral products


Parenteral products


Route of adm affects disposition biopharmacy of the drug
Route of less or more to pass through membranes .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


Parenteral products

  • i.m less or more to pass through membranes ../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
Formulation of injection less or more to pass through membranes .

  • The reference here is BP


Volume of injection
Volume of injection less or more to pass through membranes .

  • 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
The vehicle less or more to pass through membranes .

  • 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.


Parenteral products

  • Water is the ideal vehicle for most inj. less or more to pass through membranes .

  • 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


Parenteral products

  • Propylene glycol for less or more to pass through membranes .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


Parenteral products

  • Propyliodone less or more to pass through membranes . 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
Disadvantages of oily less or more to pass through membranes .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


Parenteral products

  • Contrast media ( less or more to pass through membranes .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
pyrogens less or more to pass through membranes .

  • 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


Parenteral products

  • Lipopolysaccharide less or more to pass through membranes . (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
Sources of less or more to pass through membranes .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
Physiological response to less or more to pass through membranes .pyrogens

  • Erythema at site of inj.

  • Pain in the legs & trunk

  • General discomfort

  • High temperature

  • The BP uses temp. as the basis to estimate pyrogens

    Pyrogenic→ fever producing

    Apyrogenic


Pyrogen tests are applied to
Pyrogen less or more to pass through membranes . 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
Water for injection BP less or more to pass through membranes .

  • 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


Parenteral products

  • Pyrogens less or more to pass through membranes . 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.


Parenteral products

  • Certain bacteria are able to multiply in distilled water. less or more to pass through membranes .

  • 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.


Parenteral products

  • 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.



Parenteral products


Parenteral products

  • Amylobarbitone its quality by removing dissolved gases. 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.


Parenteral products

  • Amylobarbitone its quality by removing dissolved gases. 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


Parenteral products

  • Thiopentone its quality by removing dissolved gases. 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.


Parenteral products

  • 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.


Parenteral products

  • Chlorpheniramine water for 10 min. injection BP

  • Chlorpromazine injection BP

  • Phenylephrine injection BP

  • Promazine injection BP


Water miscible vehicles
Water miscible vehicles water for 10 min.

  • 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)


Parenteral products

  • 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


Parenteral products


Parenteral products

  • Old including 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.


Parenteral products

  • Phenobarbitone including 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.


Parenteral products


Parenteral products

  • Liquid rapidly metabolized & excreted) macrogols have been recommended as prospective vehicle

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


Water immiscible vehicles
Water- immiscible vehicles rapidly metabolized & excreted)

  • 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


Parenteral products

  • Fixed oils must not contain rapidly metabolized & excreted)

  • mineral oils or soildparrafins (not metabolized by the body, cause tissue reactions, even tumors)

  • Free form rancidity (free fattr acids)

  • Free from irritation


Arachis oil
Arachis rapidly metabolized & excreted) 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
Esters rapidly metabolized & excreted)

  • 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


Parenteral products

  • 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
Alcohol intermediate in the auto-oxidative and

  • 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


Others1
others intermediate in the auto-oxidative and

  • Almound oil

  • Poppyseed oil

  • Isopropylmyristate

  • Polyethylene oleic triglycerides


Osmosis
Osmosis intermediate in the auto-oxidative and

  • 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


Parenteral products

  • If the solute is intermediate in the auto-oxidative and 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
Iso intermediate in the auto-oxidative and -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


Parenteral products

  • As the volume of the cell contents remains unchanged , intermediate in the auto-oxidative and 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.


Parenteral products


Preparation of isotonic solution
Preparation of isotonic solution can pass through it, the volume of the cell content will change, thus altering the tone of the cell

  • 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
Example can pass through it, the volume of the cell content will change, thus altering the tone of the cell

  • 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
electrolyte can pass through it, the volume of the cell content will change, thus altering the tone of the cell

  • 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


Parenteral products

  • The dissociation factor ( can pass through it, the volume of the cell content will change, thus altering the tone of the celli )

  • 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


Example1
Example can pass through it, the volume of the cell content will change, thus altering the tone of the cell

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

    58.5/1.8→-1.86

    X→ -0.52

    X= 9.09g in 1000g of water


Parenteral products


Parenteral products


Parenteral products

  • Hypertonic solutions may be bloodadm. 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.


Parenteral products

  • So hypertonic are bloodinji.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
Intrathecal blood 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
Intramuscular injections blood

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

  • Slow absorption or depot

  • Aqsusp.(insoluble form of drug) or solution or suspension in a hydrophobic vehicle.


Intracutaneous injections
Intracutaneous blood 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
Subcutaneous injections blood

  • Isotonic are preffered to reduce pain

  • Paratonics can be administered


Hydrogen ion concentration ph
Hydrogen ion concentration (pH) blood

  • 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
Increase the stability of the injection blood

  • 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
Minimize pain , irritation & necrosis blood

  • 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.


Parenteral products

  • i.t blood, 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
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
Enhance physiological activity microorganism

  • 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
Buffers microorganism

  • No toxicity

  • Compatible with medication & other added substances

  • Have high buffer capacity


Parenteral products


Suitable buffers include
Suitable buffers include: microorganism

  • Citric acid/ sodium phosphate ( digoxin)

  • Sodium acetate (insulin zinc suspension)

  • Sodium phosphate

  • Dipotassium hydrogen phosphate

  • Borates are too toxic to use in injections


Example2
Example microorganism

  • 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


Parenteral products


Parenteral products

  • The use of insoluble forms of drug to prolong action like : solution in range 6-7 with 4.5% w/v Na-citrate

  • 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
Specific gravity of the solution in range 6-7 with 4.5% w/v Na-citrate 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


Parenteral products

  • Careful choice of solution in range 6-7 with 4.5% w/v Na-citrate 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
Suspension for injection solution in range 6-7 with 4.5% w/v Na-citrate

  • 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
Wettability solution in range 6-7 with 4.5% w/v Na-citrate

  • 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


Parenteral products


Sedimentation rate
Sedimentation rate to reduce the interfacial energy btw it & the liquid

  • 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


Parenteral products


Claying
Claying because suspensions have to be reconstituted just before use

  • 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


Parenteral products

  • Partially deflocculated because suspensions have to be reconstituted just before usesusp. 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
Size & shape of particle because suspensions have to be reconstituted just before use

  • 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.


Parenteral products

  • Crystals which are because suspensions have to be reconstituted just before useisodiametric( 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
Thixotropy because suspensions have to be reconstituted just before use

  • 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


Parenteral products

  • 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-thixotropicsusp


Preparation of aq susp
Preparation of aq. permanent 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
Suspension in oily vehicle permanent

  • 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
Addition of a gelling agent permanent

  • In sterile pen G procaine with Al stearatesusp. 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
Particle size permanent

  • Crystalline zinc insulin in aqsusp → 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


Parenteral products


Emulsions for injection
Emulsions for injection permanent

  • 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


Parenteral products

  • The permanent emulsifers & stabilizers used should be non toxic

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

  • Phytomenadioneinj BP, lecithin is used as emulsifying agent


I v therapy emulsions
i.v permanent . 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


Parenteral products


Parenteral products

  • 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


Parenteral products


Colloidal dispersions solubilized products
Colloidal dispersions & would coalesce the emulsion & filtration is impossiblesolubilized 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 SorbitolInj which is a complex of ferric ions, sorbitol, & citric acid stabilized with dextran & sorbitol


Parenteral products

  • Solubilized would coalesce the emulsion & filtration is impossible 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
Quality assurance of injections would coalesce the emulsion & filtration is impossible


Microbiological preservation the use of bactericides in aqueous single dose injections
Microbiological preservation would coalesce the emulsion & filtration is impossiblethe 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


Parenteral products

  • Chlorocresol would coalesce the emulsion & filtration is impossible(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


Parenteral products


Parenteral products

  • If the membrane 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
The use of bactericide in multiple-dose container membrane

  • 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


Parenteral products

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

  • 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.


Parenteral products

  • 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
Bactericide suitable for aqueous injections heating with bactericide should not require additional bactericide

  • 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


Parenteral products


Parenteral products

  • The BP suggests : bacteria

  • 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


Parenteral products


Parenteral products

  • Care has to be taken with solubility always prove suitable

  • 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


Parenteral products

  • 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


Parenteral products


Parenteral products

  • An additional preservative is reduced by a factor not less than 10² within 7 days of challenge & no increase thereafterunnessesary 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
Bactericides suitable for oily injections reduced by a factor not less than 10² within 7 days of challenge & no increase thereafter

  • 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
Limitations to the use of bactericides reduced by a factor not less than 10² within 7 days of challenge & no increase thereafter

  • In large vol. i.vinj( ˃ 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)


Parenteral products

  • Injections reduced by a factor not less than 10² within 7 days of challenge & no increase thereafterfoi.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
Incompatibilities of common bactericides reduced by a factor not less than 10² within 7 days of challenge & no increase thereafter

  • Phenol is not compatible with procaine penicillin, quinine HCL

  • Cresol : carbacol, ergotamine

  • Phenylmercuric acetate: ascorbic acid , pethidine

  • Chlorocresol is less satisfactory, many incompatabilities


Parenteral products


Chemical stability of the medicament adjustment of ph
Chemical stability of the medicament solutions of drugadjustment 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
Addition of a reducing agent or antioxidant solutions of drug

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

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


Parenteral products

  • The reducing action of dextrose may be used, solutions of drugcarbacolinj 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
Replacement of air by inert gases solutions of drug

  • In products sensitive to O2

  • Nitrogen is satisfactory


Use of sequestering agents
Use of sequestering agents solutions of drug

  • 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


Parenteral products

  • Ethylenediamine solutions of drug 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
Inclusion of a specific stabilizer solutions of drug

  • 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


Parenteral products

  • The solutions of druginj 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
Limitations in the use of additives solutions of drug

  • 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
Particulate contamination solutions of drug

  • 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


Parenteral products


Parenteral products


Parenteral products


Parenteral products