Transcript Parenteral products

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/Intradermal
i.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
pyrogens
Pyrogenic→ fever producing
Apyrogenic
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 nonirritant 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→-1.86
X→ -0.52
X= 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, codliver, 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 preservation
the 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 medicament
adjustment 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