Parenteral Drug Delivery

ASSOC. PROF. M. SEDEF ERDAL 1

TABLE 1.1
Parenteral Drug Delivery Routes
Route Administration Volume
S.C. Low, generally <2 mL
I.M. Medium, generally <5 mL
I.V. High
Intravitreal Low, generally <0.1 mL Parenteral dosage forms are
I.D. Low, generally <0.1 mL designated either SVIs (volume 100
Intra-articular Medium mL or less) or large-volume injections
Intrathecal Low
Intraepidural Low
(volume greater than 100mL).
Intracisternal Medium
Intra-arterial High
Intracardiac Medium
Intrapleural Medium
Intraperitoneal High
Intraosseous Medium

ASSOC. PROF. M. SEDEF ERDAL 2

Pharmacopoeial requirements
for parenteral products

ASSOC. PROF. M. SEDEF ERDAL 3

Parenteral Dosage Forms 5

TABLE 1.3
Quality Aspects of Parenteral Dosage Forms
Attribute Comment
Highest level of purity for the active drug substance Highly purified “parenteral grade” excipients are available
and excipients
Formulation containing the fewest number and the The presence and amount of each excipient must be justified in regulatory filings
simplest excipients possible
Physical and chemical stability Minimal degradation during shelf life
Container-closure system with low extractable/leachable Minimize the impact of the container on product purity and stability
profile
Sterile Sterility assurance is critical for patient safety
Pyrogen free Pyrogens cause febrile response. The most potent pyrogens are bacterial endotoxins
Free from visible particulate matter Subvisible particulate matter must be excluded as much as possible as defined by
compendial requirements
Container-closure integrity Product container maintains microbiological integrity during shelf life
Injection site tolerability Formulation does not cause significant injection site irritation or tissue damage.
Products are frequently formulated as isotonic solutions
Detailed dosing and administration instructions including In clinical practice, multiple drugs are frequently administered through the same
evaluation of compatibility with coadministered drugs I.V. line to avoid the risk of an additional venipuncture

TABLE 1.4
Historical Milestones in Parenteral Drug Delivery ASSOC. PROF. M. SEDEF ERDAL 4
Year Milestone
PRODUCT QUALITY TESTS COMMON TO
PARENTERAL DOSAGE FORMS
Universal Tests

ASSOC. PROF. M. SEDEF ERDAL 5

Universal Tests
• Identification
• Identification should establish the identity of the drug or drugs
present in the preparation and should discriminate between
compounds of closely related structure that are likely to be present.
• Assay
• A specific and stability-indicating test should be used to determine
the strength (content) of the drug product.
• Impurities

ASSOC. PROF. M. SEDEF ERDAL 6

Universal Tests
• Foreign and particulate matter
• Each final container of all parenteral preparations should be inspected
to the extent possible for the presence of observable foreign and
particulate matter (visible particulates) in its contents. The inspection
process should be designed and qualified to ensure that every lot of
all parenteral preparations is essentially free from visible particulates.
• Qualification of the inspection process should be performed with
reference to particulates in the visible range and those particulates
that might emanate from the manufacturing or filling process.

ASSOC. PROF. M. SEDEF ERDAL 7

Universal Tests
• Foreign and particulate matter
• Every container in which the contents show evidence of visible
particulates must be rejected.
• The inspection for visible particulates may take place during
examination for other defects such as cracked or defective containers
or seals, or when characterizing the appearance of a lyophilized
product.
• Large-volume injections for single-dose infusion, small-volume
injections, and pharmacy bulk packages (PBPs) are subject to the light
obscuration or microscopic procedures and limits for subvisible
particulate matter.
ASSOC. PROF. M. SEDEF ERDAL 8
Universal Tests
• Sterility
• The sterility of all drug products intended for parenteral
administration should be confirmed by the use of methods as stated
in the relevant monograph
• Bacterial endotoxins
• All articles intended for parenteral administration should be prepared
in a manner designed to limit bacterial endotoxins as defined in
Bacterial Endotoxins Test 〈85〉 or Pyrogen Test 〈151〉.

ASSOC. PROF. M. SEDEF ERDAL 9

Universal Tests
• Packaging systems
• The packaging system should not interact physically or chemically with the
preparation to alter its strength, quality, or purity beyond the official or
established requirements.
• Container–closure integrity
• The packaging system should be closed or sealed in such a manner as to
prevent contamination or loss of contents. Validation of container integrity
must demonstrate no penetration of microbial contamination or gain or
loss of any chemical or physical parameter deemed necessary to protect
the product.
• Labeling
• All articles intended for parenteral administration should meet the labeling
requirements.
ASSOC. PROF. M. SEDEF ERDAL 10
Pharmacopoeial requirements
for parenteral products
General requirements

ASSOC. PROF. M. SEDEF ERDAL 11

Sterility

• All parenteral preparations are sterile preparations intended for

injection, infusion or implantation into the body.
• The requirement for sterility is vital as the method of administration
of these products bypasses the body’s natural defence systems and
barriers (such as the skin or gastrointestinal system), and introduces
the medicine directly into the bloodstream or other body tissues.

ASSOC. PROF. M. SEDEF ERDAL 12

Excipients

• Excipients may be added to parenteral preparations to serve a

number of purposes.
• They can be added to make the preparation isotonic in relation to
human blood, to adjust the pH, to increase the solubility of the drug
substance, to increase the stability of the drug substance and increase
the shelf life of the product or to act as a preservative.
• The use of excipients should not adversely affect the action of the
drug substance, or cause any side effects or toxicity at the
concentrations used in a given formulation.

ASSOC. PROF. M. SEDEF ERDAL 13

Containers

• Containers for parenteral preparations should be made, wherever

possible, from materials that are sufficiently transparent to allow the
contents to be visually inspected for particles, before use.
• Containers can be made from glass or plastic.
• Whatever the type of container, it should be effectively sealed to
prevent the enclosed medicine becoming contaminated with
microorganisms or other contaminants during storage before use.
• Containers should therefore be airtight and also preferably tamper
evident.

ASSOC. PROF. M. SEDEF ERDAL 14

Endotoxins and pyrogens
• As well as being sterile, parenteral preparations must be practically
free from endotoxins and pyrogens.
• These substances are bacterial products that may be released from
certain types of bacteria when they are alive, or after they die.
• They may therefore be present in sterile products as a by-product of
the sterilization process which kills the bacteria during manufacture.
• When they are injected into a patient, they can cause fever, and even
shock if present in sufficient quantities.
• Therefore parenteral products must comply with the test for bacterial
endotoxins or the test for pyrogens.

ASSOC. PROF. M. SEDEF ERDAL 15

Particulates
• The final general test with which certain parenteral products much
comply is for particulate contamination.
• They must be free of visible particles and contain only very low
numbers of subvisible particles.
• This is of particular importance for medicines administered
intravenously.
• Particles inadvertently injected with a medicine will travel through the venous
system to the heart and from there to the lungs.
• In the lungs, the vascular system narrows to a network of capillaries around
each alveolus, and any suspended particles may become entrapped at this
point, preventing blood from flowing, resulting in a pulmonary embolism.

ASSOC. PROF. M. SEDEF ERDAL 16

Parenteral Formulations

ASSOC. PROF. M. SEDEF ERDAL 17

Parenteral Formulations
• There are several different parenteral formulations that are available
for parenteral administration; they are as follows:
• Solutions ready for injection
• Dry, soluble products (freeze dried or powder fill) ready to combined with a
solvent prior to administration
• Suspensions ready for injection
• Dry, insoluble products ready to be combined with a solvent prior to
administration
• Emulsions
• Liquid concentrates ready for dilution prior to administration

ASSOC. PROF. M. SEDEF ERDAL 18

 The USP categorizes sterile preparations for parenteral use according
to the physical state of the product as follows:

TABLE 1.2
Nomenclature for Injectable Dosage Forms (Ref. USP 39 Chapter <1121>)
Label/Title Description
[DRUG] injection Liquid preparations that are drug substances or solutions thereof
[DRUG] for injection Dry solids that, upon the addition of suitable vehicles, yield solutions conforming in all
respects to the requirement for injections
[DRUG] injectable emulsion Liquid preparations of drug substances dissolved or dispersed in a suitable emulsion medium
[DRUG] injectable suspension Liquid preparations of solids suspended in a suitable liquid medium
[DRUG] for injectable suspension Dry solids that, upon the addition of suitable vehicles, yield preparations conforming in all
respects to the requirement for injectable suspensions
[DRUG] extended-release injectable suspension Liquid preparations of solids suspended in a suitable liquid medium and formulated in a
manner that allows the contained active pharmaceutical ingredient (API) to be available
over an extended period of time
[DRUG] for extended-release injectable suspension Dry solids that, upon the addition of suitable vehicles, yield preparations conforming in all
respects to the requirements for extended-release injectable suspensions

ASSOC. PROF. M. SEDEF ERDAL 19

Parenteral Formulations
• Developing these different types of formulations depends on the
nature of the drug itself with respect to its physical and chemical
characteristics and on certain therapeutic considerations.
• Route of administration,
• Area of administration,
• Onset of action,
• Rate of drug release, and
• Shelf life.

ASSOC. PROF. M. SEDEF ERDAL 20

Parenteral Formulations
• If a drug is unstable in solution, it may be prepared as a dry powder or as a
suspension.
• If the drug is unstable in water, that solvent may be replaced in part or
totally by a proper co-solvent.
• If the drug is insoluble in water, an injection may be prepared as an
aqueous suspension, or as a solution in a suitable nonaqueous solvent,
such as a vegetable oil.
• If an aqueous solution is desired, a water-soluble salt form of the insoluble
drug is frequently prepared.
• The onset and duration of action of a drug may be controlled by its
chemical form, the physical state of the injection, and the vehicle.

ASSOC. PROF. M. SEDEF ERDAL 21

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Parenteral Formulations
• Drugs that are very much soluble in body fluids generally have the
most rapid absorption and onset of action.
• Thus, drugs in aqueous solution have a more rapid onset of action than do
drugs in oleaginous solution.
• Drugs in aqueous suspension are also more rapid acting than drugs in
oleaginous suspension because of the greater miscibility of the
aqueous preparation with the body fluids after injection and the
more rapid contact of the drug particles with the body fluids.
• Oftentimes, long action is desired to reduce the frequency of
injections.
• These long-acting injections are called repository or depot preparations.

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Preparation of Parenteral Formulations
• The solutions and suspensions of drugs intended for injection are
prepared in the same general manner as solutions or suspensions,
with the following differences:
1. Solvents or vehicles must meet special purity and other standards ensuring
their safety by injection
2. The use of added substances, such as buffers, stabilizers, and antimicrobial
preservatives, falls under specific guidelines of use and is restricted in
certain parenteral products. The use of coloring agents is strictly prohibited
3. Parenteral products are always sterilized, must meet sterility standards, and
must not exceed allowable endotoxin limits
4. Parenteral solutions must meet compendial standards for particulate matter

ASSOC. PROF. M. SEDEF ERDAL 31

Preparation of Parenteral Formulations
5. Parenteral products must be prepared in environmentally controlled
areas, under strict sanitation standards, and by personnel specially
trained and clothed to maintain the sanitation standards.
6. Parenteral products are packaged in special hermetic containers of
specific and high quality. Special quality control procedures are used to
ensure hermetic seal and sterile condition.
7. Each container of an injection is filled to a volume in slight excess of
the labeled volume to be withdrawn. This overfilling permits ease of
withdrawal and administration of the labeled volumes.

ASSOC. PROF. M. SEDEF ERDAL 32

Preparation of Parenteral Formulations
• 8. The volume of injection permitted in multiple-dose containers is
restricted, as are the types of containers (single dose or multiple
dose) that may be used for certain injections.
• 9. Specific labeling regulations apply to injections.
• 10. Sterile powders intended for solution or suspension immediately
prior to injection are frequently packaged as lyophilized or freeze-
dried powders to permit ease of solution or suspension upon the
addition of the solvent or vehicle.

ASSOC. PROF. M. SEDEF ERDAL 33

 EXCIPIENTS FOR PARENTERAL USE
• Injectable formulations are subject to a strict set of requirements.
• The formulated product has to be sterile, pyrogen free, and in the case of
solution, essentially free of visible particulate matter.
• Coloring agents are not allowed.
• An isotonic formulation is preferred, and depending on the route of
administration, some excipients may be prohibited.
• Certain drugs administered by injection, rather than orally, may pose a higher risk
for an adverse event or the drug’s effect may be especially difficult to reverse
because the injected drug bypasses natural defense barriers and is quickly
distributed throughout the body.
• The excipient must be able to withstand the rigors of the sterilization process
such as the very high temperatures required for terminal steam sterilization or
filtration and lyophilization in aseptic processing.
• All of the above factors can limit the choice of excipients available to the
formulator.
ASSOC. PROF. M. SEDEF ERDAL 34
 Solvents and Cosolvents for Injections

• Water for injection, USP

• Purified by distillation or by reverse osmosis
• Is not required to be sterile, but it must be pyrogen free
• The water is intended to be used in the manufacture of injectable products to
be sterilized after preparation.
• Water for injection should be stored in tight containers at temperatures
below or above the range in which microbial growth occurs.
• Water for injection is intended to be used within 24 hours after collection.
• It should be collected in sterile and pyrogen-free containers. The containers
are usually glass or glass lined.

ASSOC. PROF. M. SEDEF ERDAL 35

 Solvents and Cosolvents for Injections

• Sterile water for injection, USP

• Packaged in single-dose containers not larger than 1 L.
• As with water for injection, it must be pyrogen-free but does have an allowable
endotoxin level, not more than 0.25 USP endotoxin units/mL.
• It may not contain any antimicrobial agent or other added substance.
• Sterile water for injection is intended to be used as a solvent, vehicle, or diluent for
already sterilized and packaged injectable medications.
• The 1-L bottles cannot be administered intravenously because they have no tonicity.
Thus, they are used for reconstitution of multiple antibiotics.
• In use, the water is aseptically added to the vial of medication to prepare the desired
injection.
• For instance, a suitable injection may be pre-pared from the dry powder Sterile
Ampicillin Sodium, USP, by aseptic addition of sterile water for injection.

ASSOC. PROF. M. SEDEF ERDAL 36

 Solvents and Cosolvents for Injections

• Bacteriostatic water for injection

• It is sterile water for injection containing one or more suitable antimicrobial
agents.
• It is packaged in prefilled syringes or in vials containing not more than 30 mL
of the water.
• The container label must state the names and proportions of the
antimicrobial agent or agents.
• This water is employed as a sterile vehicle in the preparation of small volumes
of injectable preparations.
• Generally, if more than 5 mL of solvent is required, sterile water for injection rather than
bacteriostatic water for injection is preferred.
• The bacteriostatic agent gives the flexibility for multiple-dose vials.
• Not for use in neonates - benzyl alcohol toxicity
ASSOC. PROF. M. SEDEF ERDAL 37
 Solvents and Cosolvents for Injections

• Sodium chloride injection, USP

• Sodium Chloride Injection, USP, is a sterile isotonic solution of sodium chloride
in water for injection.
• It contains no antimicrobial agents.
• It may be used as a sterile vehicle in solutions or suspensions of drugs for
parenteral administration.

ASSOC. PROF. M. SEDEF ERDAL 38

 Solvents and Cosolvents for Injections

• Bacteriostatic sodium chloride injection, USP

• Sterile, isotonic solution of sodium chloride in water for injection
• It contains one or more suitable antimicrobial agents, which must be specified
on the labeling.
• Sodium chloride 0.9% renders the solution isotonic.
• For the reasons noted for bacteriostatic water for injection, this solution may
not be packaged in containers larger than 30 mL.
• When this solution is used as a vehicle, care must be exercised to ensure
compatibility of the added medicinal agent with the preservative or
preservatives and with the sodium chloride.
• Not for use in neonates

ASSOC. PROF. M. SEDEF ERDAL 39

 Solvents and Cosolvents for Injections

• Ringer’s injection, USP

• Sterile solution of sodium chloride, potassium chloride, and calcium chloride
in water for injection
• The three agents are present in concentrations similar to those of physiologic
fluids.
• Ringer’s is employed as a vehicle for other drugs or alone as an electrolyte
replenisher and plasma volume expander.
• Lactated Ringer’s injection, USP
• Has different quantities of the three salts in Ringer’s injection and it contains
sodium lactate.
• This injection is a fluid and electrolyte replenisher and a systemic alkalizer.

ASSOC. PROF. M. SEDEF ERDAL 40

 Solvents and Cosolvents for Injections

• Although an aqueous vehicle is generally preferred for an injection, it

may be precluded by the limited water solubility of a medicinal sub-
stance or its susceptibility to hydrolysis.
• When such physical or chemical factors limit the use of a wholly
aqueous vehicle, the pharmaceutical formulator must turn to one or
more nonaqueous vehicles.
• The selected vehicle must be
• Nonirritating, nontoxic in the amounts administered, and not sensitizing.
• It must not exert a pharmacologic activity of its own, nor may it adversely
affect the activity of the medicinal agent.

ASSOC. PROF. M. SEDEF ERDAL 41

 Solvents and Cosolvents for Injections

• The physical and chemical properties of the solvent or vehicle must

be considered and evaluated:
• Physical and chemical stability at various pH levels
• Viscosity (allowing ease of injection, suitability for use in syringes)
• Fluidity (must be maintained over a fairly wide temperature range)
• Boiling point (sufficiently high to permit heat sterilization)
• Miscibility with body fluids
• Low vapor pressure (to avoid problems during heat sterilization)
• Ease of purification and standardization.

ASSOC. PROF. M. SEDEF ERDAL 42

TABLE 8.1 fatty acid), while Polysorbate 20 is a polyoxyethylene sor
Solvents and Cosolvents ester of lauric acid (saturated fatty acid). Differences in fatty
composition could lead to potential stability differences in
Excipient Frequency Range Example product formulated with PS80 versus Polysorbate 20. This
Benzyl benzoate 3 20%–44.7% w/v Delestrogen® been demonstrated with Neupogen®, which when exposed
Castor oil 2 11.50% Delestrogen® high concentration of Polysorbate 20 exhibited substantially
Cottonseed oil 1 73.6%–87.4% w/v Depo® oxidation than when exposed to similar concentration of PS
Testosterone In other formulation studies with proteins, no such advanta
N,N- 2 6%–33% w/v Busulfex® polysorbate could be confirmed as formulation stability is
Dimethylacetamide
ecule dependent. The PS80 USP monograph may not be
Ethanol/ethanol 34 0.6%–100% Prograf®,
to meet the tightened injectable PS80 fatty acid compos
dehydrated Alprostadil
specification in the 2015 Chinese Pharmacopoeia.
Glycerin (glycerol) 17 1.6%–70% w/v Multitest CMI®
Several new excipients, such as CDs, are being evaluate
N-methyl-2- 1 a Eligrad
pyrrolidone order to increase the solubility or improve the stability of p
Peanut oil 1 a Bal in Oil® teral drugs. Currently, there are two FDA-approved paren
PEG products that utilize alpha and gamma CDs. Beta-CD is un
PEGb 5 0.15%–50% Secobarbital able for parenteral administration because it causes necros
sodium the proximal kidney tubules upon intravenous and subcutan
PEG 300 4 50%–65% VePesid® administration.37 Hydroxypropyl beta-cyclodextrin (HPβ
PEG 400 4 11.2%–67% v/v Busulfex® and sulfobutylether β-cyclodextrin (SBE-7-β-CD) have sh
PEG 600 1 5% w/v Persantine® the most promise. Captisol™ is the trade name of SBE-7-β
PEG 3350 4 0.3%–3% Depo-Medrol® and is anionic. Currently, at least eight Captisol™-based hu
PEG 4000 1 0.3%–3% Invega drug formulations are on market in the United States.
Sustenna® parenteral formulation which utilizes HPβCD (Sporanox)
Poppyseed oil 1 a Ethiodol® been approved by the FDA and at least four other inject
Propylene glycol 32 0.0025%–80% Ativan® (diclofenac, itraconazole, mitomycin and telavancin) in Eu
Safflower oil 2 5%–10% Liposyn II® Manufacturers of HPβCD and SBE-7-β-CD have establish
Sesame oil 7 100% Solganal Inj.® Drug Master File (DMF) with the FDA. A detailed revie
Soybean oil 1 10% w/v Diprivan Inj. CDs has been recently published.38,39 Overall, α- and β-CDs
Vegetable oil 2 a Virilon IM Inj.® renal toxicities at relatively low doses after parenteral adm
a Not applicable or no data available. tration and are not very suitable for IV administration; how
b PEG molecular weight not specified. HPβCD and SBE-7-β-CD are considered safe in humans
than 2 years when given for several months.40 Two addit
ASSOC. PROF. M. SEDEF ERDAL concerns when using CD are the potential 43 to accelerate
Polymeric and Surface Active Compounds product degradation and sequestering preservatives rende
41
 Solvents and Cosolvents for Injections

• Water for injection (WFI) is the most common solvent.

• WFI may be combined or substituted with a cosolvent to improve the
solubility or stability of drugs.
• The dielectric constant and solubility parameters are among the most
common polarity indices used for solvent blending.
• For more than 50% of parenteral cosolvent systems, ethanol and
propylene glycol are used either alone or in combination with other
solvents.

ASSOC. PROF. M. SEDEF ERDAL 44

 Solvents and Cosolvents for Injections

• There are significant safety concerns for use of propylene glycol in

medicinal products for infants and children below the age of 5, pregnant
women, and patients with renal and hepatic failure.
• The following is order of cosolvents hemolytic potential:
• Dimethyl acetamide < PEG 400< ethanol < propylene glycol < dimethyl
sulfoxide
• Drug degradation in the cosolvent system may result from the potential
presence of residual peroxide from the bleaching of PEG or the generation
of peroxides in PEG.
• Hence, it is important to use unbleached and/or low peroxide PEGs in the
formulation.

ASSOC. PROF. M. SEDEF ERDAL 45

 Solvents and Cosolvents for Injections

• Oils such as cottonseed, castor, safflower and soybean have

additional specifications when used in parenterals.
• These specifications include
• saponification value,
• iodine number,
• test for unsaponifiable matter,
• test for free fatty acid,
• solid paraffin test at 10°C, and
• acid value.

ASSOC. PROF. M. SEDEF ERDAL 46

 Solvents and Cosolvents for Injections

• Oils are used to dissolve drugs with low aqueous solubility and
provide a mechanism to slowly release drug over a long period of
time.
• In total, parenteral nutrition products oils serve as a fat source and as
carriers for fat-soluble vitamins.
• Two important concerns when using fixed oils in injectable products
are (i) oil degradation, which leads to rancidity and production of free
fatty acids, and (ii) the presence of mineral oil or paraffin which the
body cannot metabolize.

ASSOC. PROF. M. SEDEF ERDAL 47

 are packaged in multiple-dose containers to pre- such as nitrogen, to enhance the stability of the
vent the growth of microorganisms regardless of product by preventing a chemical reaction
the method of sterilization employed, unless between oxygen and the drug.

TABLE 15.1 SOME INJECTIONS IN OIL

INJECTION OIL CATEGORY
Dimercaprol Peanut Antidote to arsenic, gold, and mercury poisoning
Estradiol cypionate Cottonseed Estrogen
Estradiol valerate Sesame or castor Estrogen
Fluphenazine decanoate Sesame Antipsychotic
Fluphenazine enanthate Sesame Antipsychotic
Hydroxyprogesterone caproate Castor Progestin
Progesterone in oil Sesame or peanut Progestin
Testosterone cypionate Cottonseed Androgen
Testosterone cypionate and estradiol cypionate Cottonseed Androgen and estrogen
Testosterone enanthate Sesame Androgen
Testosterone enanthate and estradiol valerate Sesame Androgen and estrogen

ASSOC. PROF. M. SEDEF ERDAL 48

[Link] 444 10/22/2009 9:02
 TABLE 8.2
Solubilizing, Wetting, Suspending, Emulsifying, or Thickening Agents
Excipient Frequency Range Example
Acacia 2 7% Tuberculin old test®
Aluminum monostearate 1 2% Solganal Inj.®
Carboxy methyl cellulose 4 0.50%–0.55% Bicillin®
Carboxy methyl cellulose, sodium 21 0.15%–3.0% Nutropin Depot®
(crosscarmellose sodium)
Cremophor ELa 3 50%–65% w/v Sandimmune®
CD, Gamma 1 5.0% Cardiotec
CD, Alpha 1 0.14% Edex
HPβCD 2 16%–40% Sporanox
Sulfobutylether CD sodium 3 15%–29.4% Geodon
Desoxycholate sodium 1 0.4% w/v Fungizone®
Egg yolk phospholipid 3 1.2% Cleviprex®
Gelatin, hydrolyzed 1 16% w/v Cortone®
Lecithin 8 0.4%–1.2% w/v Diprivan®
Polyoxyethylated fatty acid 1 7% w/v AquaMephyton®
PS80 (Tween 80) 72 0.001%–100% Aquasol A parenteral®,
Taxotere®
Polysorbate 20 (Tween 20) 22 0.001%–0.4% Calcijex®
PEG 40 castor oilb 1 11.5% v/v Monistat®
PEG 60 castor oilc 1 20% w/v Prograf®
Poloxamer 188 (Pluronic F68) 5 0.005%–0.3% Norditropin
Povidone (polyvinyl pyrrolidone, 7 0.5%–0.6% w/v Bicillin®
crosspovidone)
Sodium dodecyl sulfate 1 0.018% w/v Proleukin®
(Na lauryl sulfate)
Sorbitol 3 25%–50% Aristrospan®
Triton X-100 (octoxynol-9) 1 0.0085% w/v Fluarix®
a Cremophor EL, Etocas 35, polyethoxylated castor oil, polyoxyethylene 35 castor oil.
b PEG 40 castor oil, polyoxyl 40 castor oil, castor oil POE-40, Croduret 40, polyoxyethylene 40 castor oil, Protachem CA-40.
c PEG 60 hydrogenated castor oil; Cremophor RH 60, hydrogenated castor oil POE-60, Protachem CAH-60.

ASSOC. PROF. M. SEDEF ERDAL 49

TABLE 8.3 2. Reducing agents: They have a lower redox potential
Polymeric and Surface Active Compounds

• Viscosity enhancing and suspending agents such as carboxy methyl

cellulose, sodium carboxy methyl cellulose, acacia, povidone,
hydrolyzed gelatin and sorbitol.
• Solubilizing, wetting, or emulsifying agents such as Cremophor EL,
sodium desoxycholate, Polysorbate 20 or 80, poloxamer-188, PEG 40
castor oil, PEG 60 castor oil, sodium dodecyl sulfate, lecithin, or egg
yolk phospholipid.
• Gelling agent such as aluminum monostearate which is added to fixed
oil to form a viscous or gel-like suspension medium.
• Complexing agents like cyclodextrins (CDs).
ASSOC. PROF. M. SEDEF ERDAL 50
• Polysorbate 80 (Tween 80) is the most common and versatile solu-
bilizing, wetting and emulsifying agent.
• Concerns with polysorbates include the residual peroxides levels and
providing protection from light and air to prevent further oxidation.

ASSOC. PROF. M. SEDEF ERDAL 51

• Several new excipients, such as CDs, are being evaluated in order to
increase the solubility or improve the stability of parenteral drugs.
• Hydroxypropyl beta-cyclodextrin (HPβCD) and sulfobutylether β-
cyclodextrin (SBE-7-β-CD) have shown the most promise.

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Chelating Agents
Excipient Frequency Range Example
Calcium disodium EDTAa 11 0.01%–0.1% Wydase®
Disodium EDTA 48 0.01%–0.11% Calcijex®
Sodium EDTA 1 0.20% Folvite®
Calcium versetamide Na 1 2.84% w/v OptiMARK®
Calteridol 1 0.023% w/v Prohance®
DTPAb 3 0.04%–1.2% Omniscan™
a EDTA, Ethylenediaminetetraacetic acid.
b DTPA, Diethylenetriaminepentaacetic acid; Pentetic acid.

ASSOC. PROF. M. SEDEF ERDAL 59

 TABLE 8.4
Antioxidants and Reducing Agents
Excipient Frequency Range Example
Acetone sodium bisulfite 4 0.2%–0.4% w/v Novocaine®
Argon - 100% Used to fill headspace of lyophilized or
liquid products. TechneScan MAG3®
Ascorbyl palmitate 1 Visudyne®
Ascorbate (sodium/acid) 10 0.1%–4.8% w/v Vibramycin®
Bisulfite sodium 31 0.02%–0.66% w/v Amikin®
Butylated hydroxy anisole (BHA) 3 0.00028%–0.03% w/v Aquasol A®
Butylated hydroxy toluene (BHT) 4 0.00116%–0.03% w/v Aquasol A®
Cystein/cysteinate HCl 4 0.07%–1.3% w/v Acthrel®
Dithionite sodium 1 0.10% Numorphan®
(Na hydrosulfite, Na sulfoxylate)
Gentisic acid 1 0.02% w/v OctreoScan®
Gentisic acid ethanolamine 1 2% M.V.I. 12®
Glutamate monosodium 1 0.1% w/v Varivax®
Glutathione 1 0.01% w/v Advate®
Formaldehyde sulfoxylate sodium 10 0.075%–0.5% w/v Terramycin solution
Metabisulfite potassium 1 0.10% Vasoxyl®
Metabisulfite sodium 33 0.02%–1% w/v Intropin®
Methionine 5 0.01%–0.15% Depo-subQ provera
Monothioglycerol (thioglycerol) 8 0.1%–1% Terramycin solution
Nitrogen - 100% Used to fill headspace of lyophilized or
liquid products
Propyl gallate 3 0.02% Navane®
Sulfite sodium 8 0.05%–0.2% w/v Enlon®
Tocopherol alpha 2 0.005%–0.075% Torisel
α-Tocopherol hydrogen succinate 1 0.02% w/v Fluarix®
Thioglycolate sodium 1 0.66% w/v Sus-Phrine®

It is imperative to first try controlling oxygen exposure to the for preservative use in multi-dose aqueous injections at
ASSOC. PROF. M. SEDEF ERDAL 60
product during the manufacturing process including sparging the concentration of 0.1%, but no examples of injectable products
51,52
120 Parenteral Medications

TABLE 8.5
Antimicrobial Preservatives
Excipient Frequency Range Example
Benzalkonium chloride 1 0.02% w/v Celestone Soluspan®
Benzethonium chloride 4 0.01% Benadryl®
Benzyl alcohol 90 0.75%–5% Dimenhydrinate Inj.
Chlorbutanol 19 0.25%–0.5% Codeine phosphate
m-Cresol 13 0.1%–0.315% Humalog®
Myristyl gamma-picolinium 2 0.0195%–0.169% w/v Depo-Provera®
chloride
Paraben methyl 55 0.05%–0.18% Inapsine®
Paraben propyl 45 0.005%–0.1% Xylocaine w/ Epinephrine
Phenol 55 0.15%–0.5% Calcimar®
2-Phenoxyethanol 4 0.50% Havrix®
Phenyl mercuric nitrate 3 0.001% Antivenin®
Thimerosal 50 0.003%–0.012% Atgam®

TABLE 8.6 range of 5–15 mM are used in the formulations but increasing the
Maximum Permissible Amount of Preservatives and Antioxidants buffer concentration to >50 mM will result in excessive pain on
ASSOC. sub-cutaneous injection and toxic effects due to the chelation
61 of
Excipient Maximum Limit in USPPROF.
(%) M. SEDEF ERDAL
calcium in the blood if large volume of product is injected.
 Phenyl mercuric nitrate 3 0.001%
Thimerosal 50 0.003%–0.012%

TABLE 8.6 range of 5–15 mM are u

Maximum Permissible Amount of Preservatives and Antioxidants buffer concentration to
sub-cutaneous injection
Excipient Maximum Limit in USP (%)
calcium in the blood if
Mercurial compounds 0.01 Buffers have maxim
Cationic surfactants 0.01 important to select buf
Chlorobutanol 0.50
which may be subjecte
Cresol 0.50
during processing such
Phenol 0.50
or lyophilization. Tris,
Sulfur dioxide or an equivalent 0.20
pH of buffer, made at 2
amount of the sulfite, bisulfite, or
metabisulfite of potassium or sodium
which could dramatica
drug. Similarly, the pre
may be those which sh
between 2001 and 2004 which indicated effects on reproductive not crystallize out, and
apparatus of juvenile male rats given propyl53 or butyl paraben,54 tecting the drug. For ex
but lack of effects for methyl and ethyl parabens.55 However, buffer improves the stab
more comprehensive toxicological
ASSOC. PROF. M. SEDEF data
ERDAL suggests otherwise.56 the lyophilization
62 of m
 Benzoate sodium/acid 3.5–6.9 Valium® Hydroxy
Excipients for Parenteral Use Sodium 2.5–7.0 Syntocinon®
121 trehalose), polyhydric alcohols (inositol, mannitol, ® sorbitol),
Bicarbonate, sodium 5.5–11.0 Cenolate currently u
Acetic acid 2.5–7.2 Syntocinon® glycols (PEG 3350), povidone (polyvinylpyrrolidone, ®PVP) and
Boric acid/sodium Comvax
Glacial acetic acid 3.5–7.0 Brevibloc® proteins (albumin, gelatin). Even though many lactose intolerant
Carbonate, sodium 4.0–11.0 TABLE 8.8
a fewHyperab
®
TABLE 8.7 asAmmonium
lyophilization bulking agents6.8–7.8 Bumex Injection
and also as stabilizers, and/or
® individuals can take drugs containing hundred mg of
Carbon dioxide
lactose, a sub-population is highly- sensitive to Serentil
lactose.—to fill
®
Ammonium
as buffers sulfate
include some amino acids- such as Innovar
glycine,®
alanine, Recently, Bulking Ag
Buffers and pH Adjusting Agents headspace
Ammonium hydroxide - Triostat
histidine, imidazole, arginine, asparagine and aspartic ®
acid. EMA/443893/2017 has recommended that methylprednisolone Excipient
Excipient pH Range Example Arginine commonly used lyo-additives
Other 7.0–7.4 Retavase®
are monosaccharides injections containing lactose must not be given to patients allergic
Citrate Alanine
Acetate Aspartic acidglucose, maltose, 5.0–5.6
(dextrose, Pepcid® (sucrose,
lactose), disaccharides toAcid
cow’s milk protein and the2.5–9.0
company has been requested
DTIC-Dome ® to Albumin
Sodium 2.5–7.0 Syntocinon® Benzene sulfonic
trehalose), acid
polyhydric 3.25–3.65
alcohols Nimbex® sorbitol),
(inositol, mannitol, reformulate
Sodium the lyophilized product.
3.0–8.5 Amikin ®
Albumin (hu
Acetic acid 2.5–7.2 Syntocinon® Benzoate(PEG
glycols sodium/acid
3350), povidone3.5–6.9 Valium® PVP) and
(polyvinylpyrrolidone, Hydroxyethyl starch (hetastarch)
Disodium 6.1 and pentastarch,
Cerezyme which
® are Amino acids
Glacial acetic acid 3.5–7.0 Brevibloc® Bicarbonate,
proteins sodium gelatin). Even
(albumin, 5.5–11.0 Cenolate®intolerant
though many lactose currently
Trisodiumused as plasma expanders
6.1 in commercial
Cerezymeinjectable
®
Arginine (L)
Ammonium 6.8–7.8 Bumex Injection® Boric acid/sodium
individuals can take drugs containing a fewComvaxhundred ®
mg of Diethanolamine 9.5–10.5 Bactim IV® Aspargine
Ammonium sulfate - Innovar® Carbonate,a sodium
lactose, 4.0–11.0
sub-population is highly Hyperab Recently,
sensitive to lactose. ® TABLE 8.8
Glucono delta lactone 5.5–7.0 Quinidine gluconate Aspartic acid
Ammonium hydroxide - Triostat® Carbon dioxide
EMA/443893/2017 -
has recommended Serentil®—to fill
that methylprednisolone Glycine/glycine
Bulking Agents, HClProtectants, and
2.5–10.8
Tonicity AdjustersHep-B Gammagee® Calcium chlo
Arginine 7.0–7.4 Retavase® injections containing lactose must not be given to headspace
patients allergic Histidine/histidine HCl
Excipient
5.0–6.5 Doxil®
Example CD-alpha
Aspartic acid 5.0–5.6 Pepcid® to cow’s milk protein and the company has been requested to Hydrochloric acid Broad range Amicar® CD-gamma
Citrate Alanine
Benzene sulfonic acid 3.25–3.65 Nimbex® reformulate the lyophilized product. Hydrobromic acid 3.5–6.5 Thrombate III®
Scopolamine Dextran 40
Acid 2.5–9.0 DTIC-Dome® Albumin 2.7–5.8 Bioclate Innovar®
®
Hydroxyethyl starch (hetastarch) and pentastarch, Lactate sodium/acid
Benzoate sodium/acid 3.5–6.9 Valium® Sodium 3.0–8.5 Amikin®which are Albumin (human) Botox ® Dextrose
Bicarbonate, sodium 5.5–11.0 Cenolate® currently used as plasma expanders in commercial injectable Lysine (L) - Eminase® Gelatin (cros
Disodium 6.1 Cerezyme ®
Amino acids Havrix ®
Boric acid/sodium Comvax® Maleic acid 3.0–5.0 Librium® Gelatin (hyd
Trisodium 6.1 Cerezyme® Arginine (L) Activase ®
Carbonate, sodium 4.0–11.0 Hyperab ® TABLE 8.8 Meglumine 6.5–11.0 Magnevist® Lactic and g
Diethanolamine 9.5–10.5 Bactim IV® Aspargine Tice BCG ®
Carbon dioxide - Serentil®—to fill Methanesulfonic acid 3.2–4.0 DHE-45® Glucose
Bulking Agents,
Glucono delta Protectants, and
lactone Tonicity Adjusters
5.5–7.0 Quinidine gluconate Aspartic acid (L) 8.0–9.0 Pepcid Terramycin
®
headspace Monoethanolamine Glycerine
Glycine/glycine HCl 2.5–10.8 Hep-B Gammagee® Calcium chloride Xyntha®
Excipient Example
Histidine/histidine HCl 5.0–6.5 Doxil ®
Phosphate Glycine/glyc
Citrate Alanine Thrombate III® ® CD-alpha Edex®
Hydrochloric acid Broad range Amicar Acid 6.5–8.5 CardiotecSaizen ® Histidine
Acid 2.5–9.0 DTIC-Dome® Albumin Bioclate® CD-gamma ®

Hydrobromic acid 3.5–6.5 Scopolamine Monobasic Imidazole

40 potassium 6.7–7.3 Etopophos Zantac ®
Sodium 3.0–8.5 Amikin® Albumin (human) Botox® Dextran ®

Lactate sodium/acid 2.7–5.8 Innovar® Dibasic potassium 6.7–7.3 BetaseronAminosyn ® Inositol

Disodium 6.1 Cerezyme® Amino acids Havrix® Dextrose ®

Lysine (L) - Eminase® Monobasic sodium a 2.5–8.0 Pregnyl ® Lactose

Trisodium 6.1 Cerezyme® Arginine (L) Activase® Gelatin (crosslinked) Kabikinase ®

Maleic acid 3.0–5.0 Librium® Dibasic sodiumb 2.5–8.3 Acthar® Zantac® Magnesium
Diethanolamine 9.5–10.5 Bactim IV® Aspargine Tice BCG® Gelatin (hydrolyzed)
Meglumine 6.5–11.0 Magnevist® Tribasic Magnesium
and sodium - Synthroid ®
Glucono delta lactone 5.5–7.0 Quinidine gluconate Aspartic acid (L) Pepcid® Lactic glycolic acid copolymers Lupron Depot ®

Methanesulfonic acid 3.2–4.0 DHE-45® Sodium Maltose

Glucosehydroxide Broad rangeIveegam®Optiray ®
Glycine/glycine HCl 2.5–10.8 Hep-B Gammagee® Calcium chloride Xyntha®
Monoethanolamine 8.0–9.0 Terramycin Succinate Mannitol
Histidine/histidine HCl 5.0–6.5 Doxil® CD-alpha Edex® Glycerinesodium/disodium 5.0–6.0 Tice BCGAmBisome
® ®

Sulfuric acid 3.0–7.0 Atgam® Nebcin® PEG 3350

Hydrochloric acid Broad range Amicar® Phosphate Glycine/glycine hydrochloride
CD-gamma Cardiotec® Polylactic ac
Hydrobromic acid 3.5–6.5 Scopolamine Tartrate
Histidinesodium/acid 2.5–6.2 Antihemophilic
Methergine ®
factor, human
Acid 40
Dextran 6.5–8.5 EtopophosSaizen
® ®
Tromethamine (Tris) 6.5–9.0 Optiray ® Potassium ch
Lactate sodium/acid 2.7–5.8 Innovar® Monobasic potassium 6.7–7.3 BetaseronZantac® Imidazole Helixate ®
Dextrose ®
Povidone
Lysine (L) - Eminase® Dibasic potassium 6.7–7.3 Kabikinase Aminosyn ® aInositol OctreoScanor
Sodium biphosphate, sodium dihydrogen phosphate
®
Na dihydrogen
Gelatin (crosslinked) ®
Sodium chlo
Maleic acid 3.0–5.0 Librium® Monobasic sodium a 2.5–8.0 Acthar® Pregnyl ® Lactose
orthophosphate. Caverject®
Gelatin (hydrolyzed) Sodium chol
b Sodium phosphate, disodium hydrogen phosphate.
Meglumine 6.5–11.0 Magnevist® Magnesium chloride Terramycin solution
Lactic and glycolic acid copolymers2.5–8.3 Lupron Depot
Dibasic sodium b Zantac
® ®
Sodium succ
Methanesulfonic acid 3.2–4.0 DHE-45® Tribasic sodium - Magnesium sulfate Tice BCG®
Glucose Iveegam® Synthroid® Sodium sulfa
Monoethanolamine 8.0–9.0 Terramycin Sodium hydroxide Broad range Maltose Gamimune N®
Tice BCGOptiray
®
Glycerine
ASSOC. PROF. M. SEDEF ERDAL
®
Bulking Agents, Protectants, and Tonicity Adjusters
63 Sorbitol
Succinate sodium/disodium 5.0–6.0 Atgam AmBisome® Mannitol Elspar®
Phosphate Glycine/glycine hydrochloride ®
Sucrose
® Sulfuric acid
Histidine 3.0–7.0 Antihemophilic
Nebcinfactor,
®
human
Table
PEG 3350 8.8 lists additives that are osmolality
Bioclate®
adjusters, and
 ®
Hydrobromic acid 3.5–6.5 Scopolamine Dextran 40 Etopophos®
® TABLE 8.8 sodium/acid
Lactate 2.7–5.8 Innovar® Dextrose Betaseron®
® —to fill Bulking
LysineAgents,
(L) Protectants, and Tonicity- Adjusters Eminase® Gelatin (crosslinked) Kabikinase®
ace Maleic acid 3.0–5.0 Librium ®
Excipient Example Gelatin (hydrolyzed) Acthar®
Meglumine 6.5–11.0 Magnevist ®
Lactic and glycolic acid copolymers Lupron Depot®
Alanine Thrombate III®
ome® Methanesulfonic acid 3.2–4.0 DHE-45 ®
Glucose Iveegam®
Albumin Bioclate®
Monoethanolamine 8.0–9.0 ® Terramycin Glycerine Tice BCG®
Albumin (human) Botox
me® AminoPhosphate
acids Havrix® Glycine/glycine hydrochloride Atgam®
me® ArginineAcid
(L) Activase® Histidine Antihemophilic factor, human
6.5–8.5 Saizen®
V® Aspargine Tice BCG® Imidazole Helixate®
Monobasic potassium 6.7–7.3 Zantac®
ne gluconate AsparticDibasic
acid (L)potassium Pepcid® Inositol OctreoScan®
6.7–7.3 Aminosyn®
Gammagee® CalciumMonobasic
chloride sodiuma Xyntha® Lactose Caverject®
2.5–8.0 Pregnyl®
CD-alphaDibasic sodiumb Edex
2.5–8.3
®
Zantac® Magnesium chloride Terramycin solution
CD-gamma Tribasic sodium Cardiotec
-
®
Synthroid® Magnesium sulfate Tice BCG®
mine Dextran 40 hydroxide Etopophos ®
Maltose Gamimune N®
®
Sodium Broad range Optiray®
Dextrose
Succinate sodium/disodium Betaseron
5.0–6.0
®
AmBisome® Mannitol Elspar®
®
Gelatin (crosslinked)
Sulfuric acid Kabikinase
3.0–7.0
®
Nebcin® PEG 3350 Bioclate®
®
Gelatin (hydrolyzed)
Tartrate sodium/acid Acthar
2.5–6.2
®
Methergine® Polylactic acid Lupron Depot®
st® Lactic and glycolic acid copolymers Lupron Depot ®
Tromethamine (Tris) 6.5–9.0 Optiray® Potassium chloride Varivax®
®
Glucose Iveegam ®
Povidone Alkeran®
cin a Sodium biphosphate, sodium dihydrogen phosphate or Na dihydrogen
Glycerine Tice BCG ®
Sodium chloride WinRho SD®
orthophosphate.
Glycine/glycine hydrochloride Atgam ®
b Sodium phosphate, disodium hydrogen phosphate. Sodium cholesteryl sulfate Amphotec®
Histidine Antihemophilic factor, human Sodium succinate Actimmune®
Imidazole Helixate ®
Sodium sulfate Depo-Provera®
yn® Bulking Agents, Protectants, and Tonicity Adjusters
Inositol OctreoScan ®
Sorbitol Panhematin®
® Lactose Caverject® Sucrose Prolastin®
Table 8.8
Magnesium chloride lists additives that are osmolality
Terramycin solution adjusters, and
L-Threonine Temodar®
bulking
Magnesium sulfate or lyo/cryoprotective agents.
Tice The
BCG®most common tonicity
d® Trehalose (alpha, alpha) Herceptin®
adjusters are dextrose and sodiumGamimune
Maltose [Link]
® that serve
me® Mannitol Elspar® ASSOC. PROF. M. SEDEF ERDAL 64
PEG 3350 Bioclate ®
ASSOC. PROF. M. SEDEF ERDAL 65