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Lecture 1 Parenteral Drugs Hafeli
Types of products required to be sterile
Injections: can be ready for injection or a dry solid
that must be reconstituted prior to administration
a) [Drug] Injection – drug in solution in a
suitable vehicle ready for injection
Diazepam Injection
b) [Drug] for Injection – dry solid that after
reconstitution yields a solution
Penicillin G Sodium for Injection
c) [Drug] Injectable Emulsion – drug dissolved or
dispersed in an emulsion
Diazepam Injectable Emulsion
d) [Drug] Injectable Suspension – solid drug
suspended in a liquid
Medroxyprogesterone acetate injectable
suspension
e) [Drug] for Injectable Suspension – dry solid
drug that yields a suspension upon addition of
a liquid
Imipenem/cilastatin sodium for injectable
suspension
Large and small volume parenteral solutions
(intended for IV infusion packed in PVC (glass) or
plastic (non-PVC))
a) Large volume parenterals: volume > 100 mL
b) Small volume parenterals: volume ≤ 100 mL
Essential requirements of parenterals
1) Formulations must be sterile: free of viable
microorganisms to prevent local or systemic
infections
Steam and dry heat
If heat labile: aseptic filtration; gas (ethylene
oxide); radiation
2) Formulations must be pyrogen free
Pyrogens = lipopolysaccharides or endotoxins
of bacterial origin (major component of gram
negative bacteria cell wall)
Causes immune response & fever (45-90 min
post injection latent period)
3) Formulations must be free of particulate matter
> 5-10 um can cause harm (blockage of small
blood vessels, emboli formation, granulomas)
4) Formulations must be isotonic
Tonicity adjusting agents decrease hemolysis
of blood cells & reduce pain and irritation
5) Stable for intended use
6) pH – not vary significantly
Needle size: smaller Gauge number mean larger
needle diameter
Major routes of parenteral administration Route Site Dosage form Max
volume Absorption Complications
Intradermal Superficial dermis skin layer (forearm)
Solutions Suspensions Emulsion
0.1 mL Slow and limited; used for antigen testing
Tissue irritation
Subcutaneous SC skin (thigh, upper arms, lower abd)
2 mL Slow absorption; longer onset than IM
Tissue infection; hardening; abscess formation
Intramuscular Muscle mass (buttocks, thigh, upper arm)
2.5 mL Faster absorption than SC; usually as depot for controlled release; aspirate to check for blood
Muscle contraction; nerve injury; irritation; abscess
Intravenous Into vein (forearm, hand, foot, scalp)
Solutions Emulsions
Variable Rapid response (100% bioavailability)
Hematoma; extravasation; thrombosis; phlebitis; infection
Other routes of parenteral administration Epidural Dura mater
Intra-articular Joint
Intra-arterial Artery
Intracardiac Heart
Intralymphatic Lymphatic vessel/ node
Intraperitoneal Peritoneal cavity
Intraspinal Vertebral column (epidural or intrathecal)
Intrathecal CSF at any level
Intravitreal Vitreous humor of eye
Complications of parenteral administration:
Extravasation: accidentally administer IV solution
into tissue around vein inflammation, pain,
irritation or tissue necrosis
Thrombosis: damaging inside blood vessel clot
(thrombus) thrombophlebitis (inflammation)
dislodge (embolus) embolism
Hematoma: escape of blood from vessel into tissue
Lecture 1 Parenteral Drugs Hafeli
Principles of formulation
Vehicles:
Aqueous vehicles Vehicle Description Sterility Use
Water for injection
Purified by distillation or reverse osmosis
Pyrogen free
Not required to be sterile (used w/in 24h)
Manufacturing of injectables which will be sterilized after preparation
Sterile water for injection (packages ≤ 1L)
Sterilized
Pyrogen free
Solvent for already sterilized & packaged injectables
Bacteriostatic water for injection (packages ≤ 1L)
Sterile
Pyrogen-free
Antimicrobials*
Other substances
Sterile vehicle for preparing solutions or drugs for parenteral administration
Sterile saline for injection
Isotonic saline prepared from water for injection
Sterile
* Adding antimicrobials: can use multi-dose but only in small volumes
(toxicity); NOT in neonates, epidural or intrathecal administration
Non-aqueous vehicle: delivery of hydrophobic/ hydrolytically labile drugs
Always given IM (never IV)
o EXCEPTION: lipiodol = a cottonseed oil based ethiodized oil
mixed with lipophilic anticancer drugs
Must be sterile
May cause allergic reactions
Ex: sesame, corn, peanut, soybean, cottonseed oils
o NEVER mineral oil or paraffin (not absorbed in body)
Maintenance of solubility:
Cosolvent: solubilize
drugs for injection as
aqueous solutions
precipitation if diluted
ethanol, glycerol,
propylene glycol, PEG
Surfactants: non-ionic
used to produce micellar
solutions
Polysorbates,
Cremopher EL,
pluronics
precipitation if diluted
below critical micelle
concentration
Maintenance of sterility:
preservatives are required for
multidose products
(sometimes single dose)
benzalkonium chloride,
benzoyl alcohol, parabens,
chlorobutanol,
chlorocresol, phenol,
thiomersal
Buffers, pH adjustment:
optimize solubility of drugs
(pH 4-8)
Common buffers: citric
acid/citrate; acetic
acid/acetate; phosphates;
benzoic acid/benzoate
Antioxidants/chelators:
ascorbic acid;
bisulfites/metabisulfites;
EDTA; citric acid
For hydrolytically labile
products, freeze drying
may be an option
If mixing formulations, pH
changes precipitation
Lyphophilization
Advantages Disadvantages
Removal of water at low temp.
Drug may not be stable
Ease of reconstitution Damage by the stresses
Compatible w/ aseptic operations
Not all solutes can be freeze-dried to acceptable cake
Relatively high surface area (rapid, complete reconstitution)
Cost may be issue
Temp. difference b/w chamber &
condenser + pressure differential
b/w solution in vial & vacuum
pump drives ice out of vial into
condenser
Characteristics:
Intact cake
Sufficient strength
Uniform color
Sufficiently dry & porous
Sterile
Pyrogen & particulate
free
Chemically stable (dry &
reconstituted)
Ease of administration: adjust isotonicity (not a must): NaCl & dextrose
Lecture 1 Parenteral Drugs Hafeli
Principles of formulation of parenteral suspensions
Particle size < 5 um and total solid content b/w
0.5 -5% w/v
Flow characteristics:
o Syringeability: ability to draw the susp. Into
syringe from vial w/o clogging or foaming
o Injectability: flow properties during
injection (force required for injection &
evenness of flow)
Wetting agent to prevent aggregation
(polysorbates, lecithin, pluronics)
Flocculating agent and/or suspending agent (Na
carboxymethylcellulose, methylcellulose,
polyvinylpyrrolidone, high MW PEG (3350/4000)
Nanocrystal Technology
GRAS stabilizers (generally regarded as safe)
Surface area bigger by making particles smaller
dissolve and are soluble at much higher levels
Controlled release parenterals
Oily solutions
Aqueous suspensions
Oily suspensions
Methods of Intravenous administration
IV injection (IV direct, push, bolus)
Injected using syringe directly into vein or
into port of an injection set
Max 2 mL over 1-5 min
Not all drugs (toxicity)
100% bioavailability
Often followed by a flush
Butterfly needle & heparin lock: needle
attached to tubing (2-3 inch) w/ a re-
sealable rubber port
Upon completion, the needle remains in
pt but tubing flushed w/ saline and
small amount of heparin added to
prevent clotting
Another injection can be made at a later
time
IV infusion or bolus
Continuous intravenous infusion: large volumes infused
over long period of time constant blood levels of drug
First diluted in large volume of
infusion fluid & administered at
constant rate
Exact flow rate: infusion pump
(portable; implanted; non- portable)
Non exact: drip chamber (# of drops/min + clamp to
adjust rate)
Intermittent IV infusion: administered at spaced time
intervals; diluted in mini-bag infused over 15-60 min
Piggyback administration:
Piggyback bag (2o) is hung higher than primary
bag and flows first due to hydrostatic pressure
Once secondary bag (w/ drug) done, primary bag
automatically starts to flow w/o interruption
Check valve prevents backflow of 2o solution
Central line devices – Vascular Access Devices (VAD): administration of meds & fluids; blood tests (mixed
venous oxygen saturation); measurement of CV parameters (CVP); access to other procedures; hemodialysis
1. Hickman line (central venous) catheter: surgically inserted into large central vein leading directly to heart
(jugular, subclavian, femoral) – tunnel made under skin from an exit site to insertion site; catheter sutured
2. Hickman subclavian port: similar to above but does not hang external to body (port implanted under skin)