Parenteral Drug Delivery
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• Injections may exist as either immediate
or extended-release dosage forms.
• Depending upon the volume of injection
in a package, the USP designates
injection, as either
• (i) small-volume injections or
• (ii) large-volume intravenous solutions.
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• The term small-volume injection
applies to an injection that is packaged
in containers labeled as containing
100mL or less.
• The large- volume intravenous solution
applies to a single-dose injection that is
intended for intravenous use and is
packaged in containers labeled as
containing more than 100mL.
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Formulation of Small-Volume Parenterals
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• The goal of formulation development is to have a
product that addresses all four requisites of an ideal
product from a patient point of view:
• Safe, efficacious, stable, and acceptable/tolerable.
• From the point of marketing and commercial
economics, the product should be easy to
manufacture, relatively easy to use or present, and
should have optimum shelf life at convenient storage
conditions, such as room temperature.
• Although the preferred goal of the formulation
scientist is to develop an injectable formulation that
is ready-to-use (such as an aqueous solution), a
number of codependent factors must be carefully
evaluated in determining the most appropriate type
of formulation.
• These factors are (i) biopharmaceutical
considerations, (ii) solubility, and (iii) stability.
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• The successful formulation of an injectable preparation requires
knowledge and expertise to effect rational decisions regarding the
selection of
• (i) a suitable vehicle (aqueous, nonaqueous, or cosolvent),
• (ii) added substances (buffers, antioxidants, antimicrobial agents,
chelating agents, tonicity agents, etc.), and
• (iii) the appropriate container and closure components.
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Formulation Principles
• Influence of the Route of Administration
• One of the most important considerations in formulating a parenteral
product is the appropriate volume into which the drug should be
incorporated.
• The intravenous route is the only route in which there are no strict
limits on the volumes which can be administered through hypodermic
injection.
• The choice of the solvent system or vehicle is directly related to the
intended route of administration of the product.
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Formulation Principles
• Isotonic solutions are less irritating, cause less toxicity, and eliminate
the possibility of hemolysis.
• For subcutaneous and intramuscular injections, hypertonic solutions
are often used to facilitate absorption of drug due to local effusion of
tissue fluids.
• With intravenous solutions, isotonicity becomes less important as
long as administration is slow enough to permit dilution or
adjustment in the blood.
• Intraspinal injections must be isotonic because of slow circulation of
the cerebrospinal fluid in which abrupt changes of osmotic pressure
can give rise to severe side effects.
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Formulation Principles
• Selection of Vehicle
• Most parenteral products are aqueous solutions.
• When it can be not possible to use a wholly aqueous solution for physical
or chemical reasons, the addition of solubilizing agents or cosolvents may
be necessary.
• Chemical degradation can be prevent by elimination of water partially or
totally.
• Aqueous solution formulations are prepared by simple solution of the drug
and the excipients, by in situ salt formation of the drug in the solution
(titrating against an acid or base) or by complexation of the drug with a
complexing agent.
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Formulation Principles
• Solubility and Solubilization
• The solubilization techniques for injectable formulations include
• pH adjustment,
• mixed aqueous/organic cosolvents,
• oily vehicles,
• surface active agents,
• complexation, as well as formulating the drug in emulsion, suspension,
liposomes, nanosuspensions, and
• combinations of techniques.
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Formulation Principles
• Added Substances
• These agents must frequently be incorporated into parenteral
formulas in order to provide safe, efficacious, and elegant parenteral
dosage forms.
• However, any additive to a formulation must be justified by a clear
purpose and function.
• Pharmacopeias often specify the type and amount of additive
substances that may be included in injectable products.
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CHAPTER 15 • PARENTERALS 463
TABLE 15.3 SOME INJECTIONS USUALLY PACKAGED AND ADMINISTERED
IN SMALL VOLUME
INJECTION PHYSICAL FORM CATEGORY AND COMMENTS
Botulinum toxin type A Powder for injection For temporary improvement in appearance of moderate to severe
glabellar lines associated with corrugator or procerus muscle
activity in adult patients 65 years or younger; administered IM
Butorphanol tartrate Solution Opioid agonist-antagonist analgesic; administered IM or IV for
relief of moderate to severe pain, as preoperative or preanesthe-
sia medication
Chlorpromazine HCl Solution Antipsychotic drug with antiemetic (antidopaminergic) effects;
should not be administered SQ. Injection should be IM slowly,
deep into upper outer quadrant of buttocks. Avoid injecting
directly into vein. IV route used ONLY for severe hiccoughs,
surgery, and tetanus
Cimetidine HCl Solution Histamine H2 antagonist; IM or IV for pathologic GI hypersecre-
tory conditions or intractable ulcers.
Dalteparin sodium Solution Sterile low-molecular-weight heparin for prophylaxis of deep vein
thrombosis in patients at risk who are undergoing abdominal
surgery. Available in a prefilled syringe; administered SQ
Dexamethasone Solution Glucocorticoid; IM or IV for cerebral edema, unresponsive shock.
sodium phosphate Also intra-articular, intralesional, in soft tissue of joints, bursae,
and ganglia
Digoxin Solution Cardiotonic given IM (not preferred) or IV with highly individual-
ized and monitored dosage
FM.indd ii
Dihydroergotamine Solution Alpha-adrenergic blocking agent specific for migraine, IM or IV
mesylate M. SEDEF ERDAL 12
Diphenhydramine HCl Solution Ethanolamine, nonselective antihistamine; IV or IM when PO
10/22/2009 9:53:56
impractical; indicated for type I (immediate) hypersensitivity
reactions, active treatment of motion sickness
Furosemide Solution Loop diuretic; IM or IV slowly for edema or acute pulmonary
edema
Granisetron HCl Solution 5-HT3 receptor antagonist for prevention of nausea and vomiting
during cancer therapy, including high-dose cisplatin
Heparin sodium Solution Anticoagulant IV or SQ as indicated by activated partial
prothrombin time or actuated coagulation time
Hydromorphone HCl Solution Opioid analgesic for relief of moderate to severe pain; SQ, IM, or
slow IV
Ibutilide fumarate Solution Antiarrhythmic with predominantly class III (cardiac action
potential prolongation) properties according to Vaughn Williams
Classification; infused IV undiluted or diluted in 50 mL diluent
Iron dextran Solution Hematinic agent; IV or IM for documented iron deficiency when
oral administration is unsatisfactory or impossible
Isoproterenol HCl Solution Adrenergic (bronchodilator) given IM, SQ, or IV
Ketorolac Solution NSAID for < 5 days of moderately severe acute pain that requires
tromethamine analgesia at opioid level, usually postoperatively
Lidocaine HCl Solution Cardiac depressant given IV as antiarrhythmic; also local
anesthetic epidurally, by infiltration, and in peripheral nerve
block
Magnesium sulfate Solution Anticonvulsant/electrolyte; IM or direct IV injection, IV infusion,
other IV administration for convulsive toxemia of pregnancy,
parenteral nutrition therapy, mild magnesium deficiency, and
FM.indd ii
M. SEDEF
severeERDAL
hypomagnesemia 13
10/22/2009 9:53:56
Naloxone HCl Solution Opioid antagonist; prevents or reverses effects of opioids,
including respiratory depression, sedation, hypotension; IV, IM,
and SQ
Oxytocin Solution Oxytocic, given IM (erratic) or IV obstetrically for therapeutic
induction of labor
Phenytoin sodium Solution Anticonvulsant; IM (erratic absorption) prophylaxis for neurosur-
gery or slow IV for status epilepticus
Phytonadione Dispersion Vitamin K (prothrombogenic) for hemorrhage. Aqueous
dispersion of phytonadione, a viscous liquid
Procaine penicillin G Suspension Anti-infective; IM for moderately severe infections of penicillin
G-sensitive microorganisms
Prochlorperazine Solution Antidopaminergic; IM or IV for control of severe nausea and
edisylate vomiting associated with adult surgery
Propranolol HCl Solution Beta-adrenergic receptor blocker for hypertension. Oral dosage
(tablets) is usual; IV administration is reserved for life-threatening
arrhythmias and those occurring under anesthesia
Sodium bicarbonate Solution Electrolyte; IV, undiluted or diluted for cardiac arrest, less urgent
forms of metabolic acidosis
Sumatriptan succinate Solution Selective 5-hydroxytryptamine1 receptor, subtype agonist, for
acute migraine with or without aura. Self-administered SQ from
unit-of-use syringe, SELFdose unit
Verapamil HCl Solution Calcium channel blocker; slow IV over at least 2 min for
supraventricular tachyarrhythmias
FM.indd ii
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Special Types of Parenterals
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Parenteral Suspensions
• A parenteral suspension is a dispersed, multi-phased, heterogeneous
system of insoluble solid particles intended principally for
intramuscular and subcutaneous injection.
• Suspension formulation is desired when the drug is too insoluble or
unstable to be formulated as a solution, as well as when there is a
need to retard or control the release of drug from a suspension.
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Parenteral Suspensions
• The desirable parenteral suspension is sterile, stable, resuspendable,
syringeable, injectable, and isotonic/nonirritating.
• Because a delicate balance of variables is required to formulate a
suitable product, a suspension is one of the most difficult parenteral
forms to prepare.
• Such a product must not cake during shipping and storage and should
be easy to suspend and inject through an 18–21 gauge needle
throughout its shelf life.
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Parenteral Suspensions
• To accomplish these objectives, it is essential to control the
crystallization, reduce particle size (micronization), and sterilize the
drug substance.
• Additionally, it is important to manage the processes associated with
wetting the drug with surfactants, aseptic dispersion and milling, and
the final filling into containers.
• Uniform distribution of the drug is required to ensure that an
adequate dose is administered to the patient.
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Parenteral Suspensions
• Injectable suspensions may be made with either vegetable oils or
aqueous vehicles.
• Many contain low concentrations of solids (5% or less) but a few, such
as procaine-penicillin G, may contain up to 58% w/v solids.
• Therefore, properties such as resuspendability, zeta potential,
rheology, and particle size distribution become important, and often
need to be monitored as a part of a stability program for these
products.
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Parenteral Suspensions
• Parenteral suspensions can exhibit instability due to crystal growth,
caking, and interactions between the product and its packaging.
• When particles interact to form clumps or aggregates, the process is
termed flocculation or agglomeration.
• The size of individual particles may also change due to temperature
fluctuation during storage and/or polymorphic changes.
• For example, if the solubility of a drug is very temperature dependent,
individual crystals can dissolve or grow in size depending on the
circumstances encountered.
• If the rate of absorption or injectability of the drug depends on the particle
size distribution of the dispersed insoluble drug, the intended performance of
the product may be altered.
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the rate of absorption or injectability of Partial List of Ingredients Used in Aqueous Parenteral Suspensions
particle size distribution of the dispersed
Suspending Agents
ded performance of the product may be
Aluminum monostearate
limitations of, and difference between Gelatin (nonantigenic)
Mannitol
suspensions and other suspensions have
Povidone
]. The requirements
Sodium carboxymethylcellulose
i) microbiological purity, (ii) ingredients
Sorbitol
like all parenterals, involve sterility and Surfactants
Lecithin (soybean)
arenteral suspensions in the current USP Polyoxyethylene-polyoxypropylene ethers
injectable suspensions can be illustrated Polyoxyethylene sorbitan monolaurate
ples. Sterile Ampicillin for Suspension, Polysorbate 80
er to which an aqueous diluent is added Silicone antifoam
Sorbitan trioleate
ample of a ready-to-use suspension in
Solubilizing Agents
nsion, USP and insulin zinc suspension, PEG 300
PG
pH Adjustment
Citric acid
an antimicrobial agent, a surfactant for
Sodium citrate
crystal growth (by reducing free surface
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Parenteral Suspensions
• Sterile Ampicillin for Suspension,
USP, represents a powder to which
an aqueous diluent is added to
make an injectable suspension.
• Sterile aurothioglucose suspension,
USP, is an example of a ready-to-use
suspension in vegetable oil.
• Aqueous ready-to-use suspensions
include betamethasone acetate
suspension, USP and insulin zinc
suspension, USP.
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Parenteral Suspensions
• Two basic methods are used to prepare parenteral suspensions
• (i) sterile vehicle and powder are combined aseptically
• (ii) sterile solutions are combined and the crystals are formed in situ.
• In the first method, an aqueous vehicle containing the water-soluble components
are heat sterilized, when possible or filtered through a 0.22 μm sterilizing
membrane filter into a presterilized mixing/filling tank.
• The sterile drug powder is gradually added to the sterile solution, aseptically, while mixing.
• The sterile drug powder, in turn, is obtained by aseptically filtering a solution of the drug
through a sterilizing membrane into a sterile vessel into which a presterilized solution of
antisolvent is introduced causing the drug to crystallize.
• The crystals or powder are separated aseptically by filtration or centrifugation, washed,
dried, and sized through milling.
• After all tests have been completed on the bulk material, it is aseptically filled.
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Parenteral Suspensions
• In the second method, the vehicle is prepared and sterilized by filtration.
• The drug is dissolved separately in a nonaqueous solvent and sterilized by
filtration.
• The sterile drug solution is aseptically added to the sterile vehicle, causing
the drug to crystallize.
• The resulting suspension is then diluted with sterile vehicle, mixed, the
crystals are allowed to settle, and the supernatant solution siphoned off.
• The suspension is then brought to volume and filled in the normal manner.
• In few cases, the filled vials may be subjected to terminal sterilization if
chemical properties and particle size characteristics remain unchanged
post-sterilization.
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Parenteral Suspensions
• Rheologically, an injectable suspension can present some formidable
challenges.
• While a suspension can usually be formulated so that it can be filled,
shipped, and injected, it is frequently difficult to formulate a product
in which these three qualities remain relatively unchanged
throughout its shelf life.
• Rheological evaluation should be done with a rheometer.
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Parenteral Suspensions
• The flow properties of parenteral suspensions are
typically characterized based on syringeability or
injectability.
• Syringeability encompasses the handling
characteristics of a suspension during drawing and
manipulation in a syringe, including tendencies for
clogging and foaming, as well as the accuracy of dose
measurement.
• Injectability, on the other hand, refers to the properties of the suspension during
injection, such as the pressure or force required for injection, the uniformity of flow,
aspiration qualities, and resistance to clogging.
• These syringeability and injectability characteristics are closely linked to viscosity and
particle characteristics.
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Examples of Injectable Suspension Formulations in the Market
Dexamethazone/Decadron® Medroxyprogesterone Acetate/ Triamcinolone Acetonide/
Component (8 mg/mL) Provera® (100 and 400 mg/mL) Kenalog® (10 and 40 mg/mL)
Surfactant Polysorbate 80 Polysorbate 80 Polysorbate 80
Suspending Sodium CMC PEG 3350 Sodium CMC
agent
Antimicrobial Benzyl alcohol Parabens Benzyl alcohol
agent
Antioxidant Sodium bisulfite - -
Others Disodium edetate, sodium Sodium chloride Sodium chloride
chloride, creatinine
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