PHAR635

Parenteral Dosage Forms

Instructors: Dr. Tarek Jenani
Dr. Faten Hamed

Chapter 2
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Small-Volume and Large-Volume Parenterals 1
 Large Volume Parenterals (LVP)
 Requirements:
 Sterile, non pyrogenic aqueous solutions, Free from
particulate matter
 packaged in a single dose container with a capacity of 101ml
or more.
 LVPs must not contain bacteriostatic agents or other
pharmaceutical additives except the basic necessary
ingredients.
 Clear solution except fat emulsion
 Isotonic but hypertonic also administered in TPN.
 Administered by IV infusion to replenish body fluids or
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electrolytes or to provide nutrition. 10/6/2021
 Properties of Parenteral Products
 Because parenteral products are administered directly
into a patient’s blood supply, these solutions must have
certain chemical properties or characteristics that render
them safe for patient administration
 Some characteristics include:
 pH value
 Osmolarity
 Osmolality
 Tonicity
 Compatibility of CSP additives

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 Properties of Parenteral Products
 pH Value
 The degree of alkalinity or acidity of a solution is
referred to as its pH value and is measured on a scale from
0 to 14
 Any solution with a pH of < 7.0 is considered to be acidic
 Any solution with a pH > 7.0 is considered to be alkaline
 A solution with a pH of 7.0 is considered to be neutral
 Human blood plasma has a pH of 7.4, which is slightly
alkaline
 The pH of blood plasma must be maintained for optimal
health
 Some facilities inject a buffer solution, such as sterile
sodium bicarbonate, into the CSP to neutralize the
pH and prevent patient discomfort.
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 Properties of Parenteral Products
pH Value
 IV fluids with a pH value of less than 3.5 or greater than 7.5
may damage blood vessels or cause a disruption of normal
cell function.
 Standard IV base solutions—such as dextrose 5% in water
(D5W), lactated Ringer’s (LR), and normal saline (NS):
➢ have pH values ranging from 3.5 to 6.2

 In some instances, these ≠ neutral solutions can cause a

burning or stinging sensation when injected into a patient’s
vein.
 This problem may be compounded when the CSP contains
5 an acidic electrolyte such as potassium chloride. 10/6/2021
 Properties of Parenteral Products
 Osmolarity and Osmolality:
 Osmolarity is a measure of the number of milliosmoles of
solute per liter of solution (mOsm/L)
 Osmolarity refers to the osmotic pressure applied by a
solution across a cell wall.
 Osmotic pressure is the pressure required to maintain
equilibrium within the cells.
 Osmolality is a measure of the number of milliosmoles
of solute per kilogram of solvent (mOsm/kg).
 Osmolality refers to the number of ions or molecules
in a solution.
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 Properties of Parenteral Products
 Osmolarity and Osmolality:
 Osmolarity and osmolality affect the flow of fluid into and
out of cells within the body
 To maintain optimal health, the cells should be maintained
in a state of equilibrium
 CSPs must be neither hyperosmotic nor hypoosmotic
 this state of equilibrium is called isoosmotic, meaning
that the solution has relatively the same number of
dissolved particles and the same osmotic pressure as
human blood plasma.

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 Properties of Parenteral Products
 Tonicity
 Tonicity refers to the way that cells or tissues respond to
surrounding fluid
 Cells within the human body have a semipermeable membrane
through which fluid and solutes move in and around.

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 Properties of Parenteral Products-Tonicity
 Based on the movement of fluid and solutes, the tonicity of a solution
can be classified as hypertonic, hypotonic, or isotonic.
 Hypertonic solution contains a greater number of dissolved
particles than human blood plasma
 If cells are subjected to a hypertonic solution, water will be
drawn out of the cells, causing the cells to shrink.
 Hypotonic solution contains fewer dissolved particles than
human blood plasma
 If cells are subjected to a hypotonic solution, water will be
drawn into the cells, causing the cells to swell.
 Both situations are potentially damaging to the cells and may be
harmful to a patient.
 Isotonic solution contains a number of dissolved particles
equivalent to human blood plasma.
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 Properties of Parenteral Products-Tonicity
 In addition to causing ulceration or other damage to the
blood vessel or surrounding tissue
 The administration of solutions that are either hypertonic
or hypotonic could lead to cardiovascular collapse or
overload, resulting in serious injury or death.
 Total parenteral nutrition (TPN) and other hypertonic
solutions are generally administered into larger veins such
as the subclavian vein or the superior vena cava
 these larger veins have significantly more blood flowing
through them and can more easily accommodate the
hypertonic solution

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 Properties of Parenteral Products -Tonicity

 Unlike hypertonic solutions, hypotonic solutions, are rarely

administered to patients
 Occasionally, critical care patients who are experiencing
diuresis are treated with these solutions to replace the
high volume of fluid output without significantly increasing
plasma sodium concentration (PNa)
 These patients must be monitored closely to ensure that
they do not develop a potentially life-threatening
electrolyte imbalance such as hyponatremia
(Dilutional)
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 Physical and Chemical Compatibilities
 Compatibility is the ability to combine one or more base
components or additives within a solution, without creating a
resultant change in the physical or chemical properties of any of the
solution components or additives.
 It is the responsibility of the pharmacist to understand the physical
and chemical compatibilities of the additive in the solution or liquid
in which it is placed.
 A combination that results in formation of insoluble material or affects the
efficacy or potency of the therapeutic agent of the vehicle is not acceptable,
this undesirable change is called incompatibility
 For example, deaths were associated with the administration of
calcium and phosphate in TPN (certain precautions should be
taken)
 It is also important to be alert for incompatibilities associated with
multiple infusions co-administered to a patient.
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 A typical nursing question may be, “Can the dopamine drip be
run in with the heparin drip?”
To answer these questions, the pharmacist must know about
parenteral therapy and be aware of incompatibilities.
Numerous references e.g.,
Handbook on Injectable Drugs,
King’s Guide to Parenteral Admixtures

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 Examples of LVP
Hyperalimentation Solution (TPN):
 Administration of large amount of nutrients to patients who
unable to take food orally, at caloric intake of up to 4000
kcalories/day
 Use of Subclavian vein cannulation :
 Infusion of Hypertonic solution.
 Formulation :
 Mixture of dextrose, amino acids, water, lipids,
electrolytes, vitamins and minerals

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 Examples of LVP
Cardioplegic Solutions:
 Are LVP used in heart surgery to prevent injury to
myocardium during reperfusion, as well as to maintain
bloodless operating field.
 Administered in cold form.
 Slightly alkaline to compensate metabolic acidosis.
 Hypertonic.

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 Examples of LVP
Peritoneal Dialysis Solution: (PD)
1. Sterile
2. Nonpyrogenic
3. Contain no bacteriostatic or antimicrobial agents or added
buffers
 Infused continuously into abdominal cavity, bathing peritoneum &
are then continuously withdrawn.
 The peritoneal membrane filters waste and fluids from the blood
into the solution.
 The solution containing the waste is drained from the
peritoneum after several hours and replaced with fresh solution

 Use:
 Removal of toxic substances from body
 To aid and accelerate excretion normal
 To treat acute renal insufficiency
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 Examples of LVP
The disadvantages of PD include:
 Must schedule dialysis into your daily routine, seven days a
week.
 Requires a permanent catheter, outside the body.
 Runs the risk of infection/peritonitis.
 May gain weight/have a larger waistline.
 Very large people may need extra therapy.
 Need ample storage space in your home for supplies

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 Examples of LVP
Irrigating solutions :
 To irrigate, flush & aid in cleansing body cavities &
wounds.
 Certain IV solution(Normal Saline) may be used as
irrigating solution, but solution designed as irrigating
solution should not be used parenterally.

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 Small Volume Parenterals (SVP)
 USP definition: “ an injection that is packaged in
containers labeled as containing “100 ml or less”
 SVP are sterile products packaged in vials, ampoules,
 They contain antibacterial preservatives, buffers, solubilizers,
antioxidants, and other pharmaceutical additives/excipients.
 Types of SVP:
1. Solutions
2. Suspensions
3. Emulsions
4. Dry powders

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 Solutions
 Most injectables are solution.
 Sterile, typically used for delivering medications at a
controlled infusion rate
 Most common solutions of 5% dextrose, normal saline,
0.45% normal saline
 Dextrose contributes to meet energy needs and saline
contributes sodium, an electrolyte that maintains fluid
balance and cellular functions.

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 Suspensions
 Parenteral suspension is a dispersed, multi-phased,
heterogeneous system of insoluble solid particles intended
principally for IM and SC injection.
 Suspension give prolong drug release.
 Is one of the most difficult parenteral forms to prepare.
 Requires following additives wetting agent, suspending agent,
buffering agent, preservative, antioxidant, tonicity agents
 Example of ingredients used in aqueous parenteral
suspensions:
 Suspending agent Gelatin, mannitol, povidone
 Surfactants Lecithin, polysorbate 80
 Solubilizing agents Propylene glycol
 PH adjustment Citric acid, sodium citrate

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 Suspensions
 Usually contain between 0.5% and 5% solids,
 Certain antibiotic preparations (for example procaine Penicillin G)
may contain up to 30% solids
 Particle size of drug should be small, less than 5 micrometer and
uniform for either IM and SC administration because of :
 Drug release
 Predictable rate of dissolution
 Uniform rate of sedimentation
 Parenteral suspension product must not cake during shipping and
storage and should be:
 easy to suspend and inject through an 18 to 21 gauge needle
throughout its shelf life.

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 Emulsions
 An emulsion is a heterogenous dispersion of one immiscible
liquid in another, with one or more emulsifying agents
 The main problem is the maintained of uniform oil droplets
of 1-5µ size as internal phase.
 The important aspect is selection of emulgent.
 The emulsion must be stable to autoclaving.
 Elevated temperature tend to produce coalescence of
dispersed phase & excessive shaking cause acceleration of
rate of creaming.
 Small amount of gelatin, dextran & microcrystalline
cellulose added to stabilize the emulsion.
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 Dry Powders
 Many drugs are too unstable either physically or chemically
in an aqueous medium to allow formulation as a solution,
suspension or emulsion.
 Instead, the drug is formulated as a dry powder that is
reconstituted by addition of water before administration.
 The reconstitution product is usually an aqueous solution but
occasion it may be aqueous suspension.
 Eg:-Ampicillin Trihydrate

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 Strategies for Formulating Unstable Molecules

➢ Water Removal
 The most common mechanism of instability in
parenteral formulations is hydrolysis
 Regardless of whether the formulation is a true
solution, co-solvent solution, emulsion, or contains a
complexing agent, the largest component of the
formulation is likely to be water
 Frequently, the only formulation strategy that will
result in adequate stability is water removal
 This is usually achieved by means of lyophilization

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 Lyophilization
Process stages:
o Following standard aseptic filling, partially stoppered vials
are transferred to a sterilizable lyophilizer in which drying is
carried out.
o Sterilization of the lyophilizer is usually achieved by steam, although
it is possible to use chemical methods such as hydrogen pyroxide
o Initially the product is frozen to a low temperature
o During primary drying, a high vacuum is applied, and ice is
removed via sublimation
o In the secondary drying stage, the product is heated under
vacuum, and any remaining water is removed by desorption
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 Lyophilization

o Products with very low moisture contents (<2%) can

easily be achieved
o The process also allows vials to be backfilled with
nitrogen, usually to slightly less than atmospheric
pressure, prior to stoppering, thus creating an inert
environment within the vials
o At the end of the lyophilization cycle, the stoppers are
fully inserted into the vials before removal of the
product from the chamber

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 Case
 Patient receiving a continuous infusion of Aminophylline 1 g
in 500 mL of D5W and order written to administer
Cimetidine 300 mg/ 100 mL D5W IV piggyback every 6
hours?
 Can these two drugs be mixed together?
 Why or why not?
 If not, what advice would give to the nurse in
order not to cause any harm to the patient

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