Sterile Dosage Forms and

Delivery Systems

PARENTERALS
 Sterile dosage forms:
- various
small-volume & large-volume injectable
preparations
irrigation fluids
- intended to bathe body wounds or surgical
openings, and dialysis solutions.

 Sterility
- essential: in direct contact with
the internal body fluids/tissues, - infection
easily arises.
 INJECTIONS
 Injections
- sterile, pyrogen-free preparations intended to be
administered parenterally.
 parenteral
- injectable routes of administration.
- derived from the Greek words para (outside) and
enteron (intestine)
- additives: buffer, stabilizer, antibacterial
preservative, antioxidant
- packaged in hermetic containers
 Pyrogens
- fever-producing organic substances arising from
microbial contamination
- responsible for many of the febrile
reactions in patients following IV
injections.
 DIFF. PARENTERAL ROUTES
ADMINISTRATION
Drugs may be injected into the almost any
organ or area of the body:
 joints (intra-articular)
 joint fluid area (intrasynovial)
 spinal column (intraspinal)
 spinal fluid (intrathecal)
 arteries (intra-arterial)
 heart (intracardiac)
 vein (intravenous, IV)
 muscle (intra-muscular, IM)
 skin (intradermal, ID, intracutaneous)
 under the skin (subcutaneous, SC, sub-Q, SQ,
hypodermic, hypo)
INTRAVENOUS ROUTE
INTRVENOUS ROUTE
 Thrombus and embolus formation
- main hazard of IV infusion
-induced by intravenous needles/catheters
touching the wall of the vein and the possibility
of particulate matter in parenteral solutions.
 Thrombus
- blood clot within the blood vessel or heart
- slowing of the circulation or an alteration of the
blood or vessel wall.
 Embolus
- clot circulates carried by the blood stream
→ blood vessel (obstruction and results in a
block or occlusion - embolism)
 Intravenous drugs
Advantages:
- rapid action compared with other routes of
administration.
- Optimum blood levels achieved with accuracy
and immediacy not possible by other routes.
- lifesaving in emergencies, prompt action with
the direct placement of the drug to the circulation

Disadvantages:
- once administered it cannot be retrieved.
- drug cannot be easily removed from the
circulation in adverse drug reaction
Intravenous drugs
 part selected: veins of the antecubital area (in
front of the elbow)
- large, superficial, and easy to see and enter.

 Sterile/disinfected:
*injectable solutions, syringes and needles,
and the point of entrance
- reduces the chance of carrying bacteria from
the skin into the blood via the needle.
 infusion or flow rate for intravenous fluids
- adjusted according to the needs of patient
- expressed in mL/hour and range from 42
to 150 mL/hour.

 Intravenous drugs
- in aqueous solution
- must mix with the circulating blood and not
precipitate from solution: lead to pulmonary
microcapillary occlusion and blockage of blood
flow.

 Intravenous fat emulsions

- use: source of calories and essential fatty
acids for patients requiring parenteral nutrition
for extended periods.
 Patient-controlled analgesia (PCA)
- controls pain (surgical procedures, labor, sickle
cell crisis, and cancer), with less side effects
- minimizes variations bet. suboptimal pain
relief & overuse of opioids

ADVANTAGES:
- provides constant & uniform analgesia
- prevents pharmacokinetic and
pharmacodynamic differences between patients
from interfering with the effectiveness of
analgesia
- permits patients to medicate themselves for
breakthrough pain
 INTRAMUSCULAR ROUTE
 Intramuscular injections of drugs
- oleaginous suspension can only be administered
through this route
- effects are less rapid but longer lasting than IV
administration.
- performed deep into the skeletal muscles

 Injuries to patients are related to

*point at which the needle entered and where the
medication was deposited.
- injuries include:
*paralysis resulting from neutral damage
*abscess *cyst *embolism
*hematoma *sloughing of the skin
*scarring
INTRAMUSCULAR ROUTE
 frequently used site
- adults
*upper outer quadrant of the gluteus
maximus
- infants and young children
* deltoid muscles of the upper arm/midlateral
muscles of the thigh
 volume of medication administered :
- 5 mL in the gluteal region
- 2 mL in the deltoid of the arm.
 Z-track injection technique for IM
- stain upper tissue by sealing medications in
the lower muscle
- creates a Z pattern that blocks infiltration of
medication into the subcutaneous tissue
- injection is 2 to 3 inches deep, and 20-gauge
and 22-gauge needle is used.
 SUBCUTANEOUS ROUTE
 Use: for injection of small amounts of
medication.
 Usual route for insulin injection
 Injection beneath the skin
- in the loose interstitial tissue of the outer,
upper arm, the anterior thigh, or the lower
abdomen.
 maximum amount of medication injected
- 1.3 mL,
*greater than 2 mL will most likely cause
painful pressure.
SUBCUTANEOUS ROUTE
 Syringes used
- up to 3 mL capacities and 24-gauge to
26-gauge needles are.
 Irritating drugs and those in thick
suspension
- produce indurations, sloughing, or
abscess and may be painful
 INTRADERMAL ROUTE
 injected into the corium, the more vascular
layer of the skin just beneath the epidermis.
 substances include
- various agents for diagnostic determinations,
desensitization, or immunization.
 site for intradermal injection
-anterior forearm.
 needle employed
- short (three-eights of an inch) and narrow (23-
gauge to 26 gauge)
INTRADERMAL ROUTE
 OFICIAL TYPES OF INJECTIONS
 Injection
-liquid preparations that are drug substances or
solutions
 For Injection
-dry solids + suitable vehicles → solutions
conforming to the requirements for injections
 Injectable Emulsion
-liquid preparation of drug substance dissolved or
dispersed in a suitable emulsion medium
 Injectable suspension
-liquid preparation of solid suspended in a suitable
liquid medium
 For Injectable Suspension
-dry solid + suitable vehicle → preparation
conforming to the requirements for injectable
suspensions
Differences parenteral products &
other dosage forms
 Solvents/vehicles
- meet special purity & other standards ensuring their
safety by injection
 restricted in certain parenteral products: use of added
subs’s (buffers, stabilizers & antimicrobial
preservatives)
 Parenterals:
- always sterilized
- meet the compendial standards for particulate matter
- packaged in special hermetic containers of special &
high quality
Differences parenteral products &
other dosage forms
 Each injection container
- filled slightly in excess of the labeled volume to be
withdrawn
 volume of injection permitted in multiple-dose
containers
- restricted, as the types of containers that may be
used for certain injections
 Specific labeling regulations apply to injections
 Sterile powders intended for solution/suspensions
immediately prior to injection
- packaged as freeze-dried powders to permit ease of
soln/suspension upon the addition of the
solvent/vehicle
 SOLVENTS AND VEHICLES FOR INJECTIONS

 Water for Injection, USP

- most frequently used solvent in the large scale
manufacturer of injections
- purified by distillation or by reverse
osmosis and meets the same standards for
presence of total solids
- use: manufacture of injectable products to be
sterilized after preparation.

 Purified Water, USP

- not more than 1 mg/100 mL Water for
Injection
 Sterile Water for Injection, USP
- may contain slightly more total solids than
Water for Injection because of the leaching of
solids from the glass-lined tanks during
sterilization
- use: solvent or diluent for already sterilized
and packaged injectable medication.

 Bacteriostatic Water for Injection, USP

- sterile water for injection containing one or
more suitable antimicrobial agents.
- “not intended for neonates”
- use: only in parenterals administered in small
volumes because of the presence of
antimicrobial agents
 Sodium Chloride Injection, USP
- sterile isotonic solution of NaCl in water for injection
- use: *sterile vehicle in solutions or
suspensions of drugs for parenteral
administration
*catheter or intravenous line to
infuse fluids & medications
to maintain potency
 Bacteriostatic Sodium Chloride Injection
- sterile isotonic solution of NaCl in water
for injection
- Use: *for bacteriostatic water for
injection
*catheter or intravenous line flush
to maintain potency
 Ringer’s Injection, USP
- sterile solutions of NaCl, KCl, and CaCl2
in water for injection
- use: vehicle for other drugs/ alone as an
electrolyte replenisher and plasma volume
expander

 Lactated Ringer’s Injection

- contains NaCl, KCl, CaCl2 & Na lactate
- fluid and electrolyte replenisher
and a systemic alkalyzer
 NONAQUEOUS VEHICLES
- use: when physical or chemical factors limit the
use of a wholly aqueous vehicle
Qualities:
- nonirritating, nontoxic, and not sensitizing
- must not exert a pharmacologic activity of its
own, nor affect the activity of the medicinal agent
- physical and chemical properties evaluated and
determined:
stability at various pH levels, viscosity,
fluidity, boiling point, miscibility with body
fluids, low vapor pressure and constant purity.
 ADDED SUBSTANCES in injections

 USP permits addition of suitable substances:

antibacterial preservatives, buffers,
solubilizers, antioxidants, and other
adjuncts.

- to increase stability or usefulness (but not

interdicted in the individual monographs)
- harmless in the amounts administered
- do not interfere with the therapeutic efficacy of
the preparation or with specified assays and
tests.
 METHODS OF STERILIZATION
Sterilization
- destruction of all living organisms and their spores
or their complete removal from the preparation.
 Steam Sterilization
- conducted in an autoclave and employs steam
under pressure
- microbial destruction is caused by denaturation &
coagulation of bacterial proteins by moist heat
- Bacillus stearothermophilus: biological indicator
- applicable to pharmaceutical preparations and
materials:
*withstand the required temperatures
*penetrated but not adversely affected by
moisture
 Dry Heat Sterilization
- carried out in ovens, heated by gas or electricity
and are generally thermostatically controlled
- Bacillus subtilis: biological indicator
- use: for substances not effectively sterilized by
moist heat

 Sterilization by Filtration
- depends on the physical removal of
microorganisms by adsorption on the filter medium
or by a sieving mechanism
- use: for heat-sensitive solutions

Millipore filter
- thin plastic membrane of cellulosic esters with
millions of pores per square inch
 Bacterial Filtration
- Best suited for extemporaneous preparation of sterile
solution
advantages
- speed in the filtration of small quantities of solution
- ability to sterilize thermolabile materials
- relatively inexpensive equipment required
- development and proliferation of membrane filter
technology
- complete removal of living and dead microorganisms and
other particulate matter from the solution
disadvantage
- membrane tends to be fragile
- essential to determine that the assembly was properly
made (membrane not ruptured/flawed during assembly,
sterilization, or use).
 Gas Sterilization
- requires specialized equipment resembling an
autoclave, and many combination steam
autoclaves and ethylene oxide sterilizers
- for sterilizing heat resistant & moisture
resistant products

 Sterilization by Ionization Radiation

 - sterilization by gamma rays and by cathode
rays, but application of such techniques is
limited because of the highly specialized
equipment required and the effects of
irradiation on products and their containers
- biological indicator: Bacillus pumilus
 VALIDATION OF STERILITY
- effectiveness of thermal sterilization quantified:
*determination & calculation of F value to express
thermal death.
Biologic Indicator
- best used to validate sterility for steam
sterilization
- a characterized preparation of specific
microorganisms resistant to a particular
sterilization process
- use: to monitor a sterilization cycle and/or
periodically to revalidate the process
 Thermal Death Time
- time required to kill a particular organism under
specified conditions
 PYROGENS

 causative material of pyrogens

- a lipopolysaccharide from the outer cell wall of
the bacteria and endotoxins.
- material is thermostable and water soluble
(remain in water even after sterilization by
autoclaving or by bacterial filtration).

 common means of removing pyrogens

- by oxidizing: easily eliminate gases or
nonvolatile salts of any acidic compounds
present.
Pyrogen Test, USP

 Uses: healthy rabbits properly maintained in

terms of environment and diet before the test
 Normal, or control, temperatures are taken for
each animal
- used as the base for the determination of any
temperature increase resulting from injection of
a test solution
- rabbits used: temperatures do not differ by
more than 1ºC from each other
 Examples of sterile drugs prepared
and packaged without
pharmaceutical additives (buffers,
preservatives, stabilizers, and
tonicity agents):
 Ampicillin sodium
 Ceftizoxime sodium
 Ceftazidime sodium
 Cefuroxime sodium
 Kanamycin sulfate
 Nafcillin sodium
 Penicillin G benzathine
 Streptomycin sulfate
 Tobramycin sulfate
 Sterile drugs formulated with
pharmaceutical additives and
intended to be reconstituted prior to
injection:
 Cyclophosphamide
 Dactinomycin
 Eryhtromycin lactobionate
 Hydrocortisone sodium succinate
 Mitomycin
 Nafcillin sodium
 Oxytetracycline hydrochloride
 Penicillin G potassium
 Vinblastine sulfate
Innovations done for powders for
reconstitution
 Sometimes a liquid is packaged along with the
dry powder
 Dry powders are packaged in containers large
enough to permit proper shaking with the liquid
component
 Mix-O-vial
- incorporates the IV systems that allow
preparing small volumes infusions
extemporaneously
 Abbott ADD-Vantage System IVPB
Monovial Safety Guard
 Manufacturer: Becton Dickinson
Pharmaceutical Systems
 New IV system for use in preparing
extemporaneous small-volume infusions using
plastic minibags
 Saves time, uses fewer materials & costs less
 Integrated drug transfer with a protective shield
surrounding the attached transfer needle
PACKAGING, LABELING, AND STORAGE
OF INJECTIONS
 Single-dose container
- hermetic container for parenteral
administration as a single dose
- when opened, cannot be resealed with
assurance that sterility has been maintained

 Multiple-dose container
- hermetic container that permits withdrawal of
successive portions of the contents without
changing the strength, quality, or purity of the
remaining portion
 ASHP RISK LEVEL CLASSIFICATION OF
PHARMACY-PREPARED STERILE
PRODUCTS
Risk Level 1

1. Products
 Stored at:
- room temperature and administered within
28 hours of preparation
- under refrigerator for 7 days or less before
complete administration over a period not to
exceed to 24 hours
 Frozen for 30 days or less before complete
administration
ASHP RISK LEVEL CLASSIFICATION OF
PHARMACY-PREPARED STERILE
PRODUCTS

Risk Level 1

2. Unpreserved sterile products for administration

to one patient or batch-prepared products
- containing suitable preservatives for
administration to more than one patient

3. Products prepared by closed-system aseptic

transfer of sterile nonpyrogenic finished
pharmaceutics obtained from licensed
manufacturer into sterile final containers
obtained from licensed manufacturer
ASHP RISK LEVEL CLASSIFICATION OF
PHARMACY-PREPARED STERILE PRODUCTS
Risk Level 2

Products :
 stored beyond 7 days under refrigeration/stored
beyond 30 days frozen or administered beyond
28 hours after preparation and storage at room
temperature
 Batch-prepared without preservatives for use
by more than one patient.
 compounded by complex or numerous
manipulations of sterile ingredients obtained
from:
- licensed manufacturers in a sterile container
or reservoir obtained from a licensed
manufacturer by using closed-system aseptic
transfer
ASHP RISK LEVEL CLASSIFICATION OF
PHARMACY-PREPARED STERILE PRODUCTS

Risk Level 3
Products:
 compounded from nonsterile ingredients or
compounded with nonsterile compounds with
nonsterile components, containers, or
equipment before terminal sterilization
 prepared by combining multiple ingredients by
using an open-system transfer or open reservoir
before terminal sterilization.
 CRITERIA IN DETERMINING THE
PRODUCT’S TITLE FOR ESTABLISHED
NAMES OF INJECTABLE PRODUTCS
a. Liquids
 [Drug]Injection
- title for liquid preparations that are drug
substances or solutions thereof
 [Drug]Injectable suspension
- title for liquid preparations of solids suspended
in a suitable liquid medium
 [Drug]Injectable emulsions
- title for liquid preparations of drug substances
dissolved or dispersed in suitable emulsion
medium
 b. Solids
 [Drug]For injection
- dry solids + suitable vehicles → solutions
conforming in all respects to the requirements
for injections

 [Drug]For injectable suspension

- dry solids that + suitable vehicles
→preparations conforming to the
requirements for Injectable Suspensions
 SMALL-VOLUME PARENTERALS
 Insulin Injection (regular)
-sterile aqueous solution of insulin: the only one
administered intravenously
- prepared from beef or pork pancreas or both
or through biosynthetic means
- problems encountered:
*lipohypertrophy (buildup of fibrous
tissue) *lipodystrophy
 Human Insulin
- produced by using a special non-diseases-
forming laboratory strain of E. coli and
recombinant DNA technology
 Lispro Insulin Solution
- consists of zinc insulin lispro crystals dissolved in
a clear aqueous fluid
- created when the amino acids at positions
28 and 29 on the insulin B-chain are
reversed
 Insulin Aspart
- recombinant ultra-short acting insulin using
Saccharomyces cerevisiae (baker’s yeast) as the
production organism
 Isophane Insulin Suspension (NPH/neutral
protamine hagedorn Insulin)
 - protamine is added
- sterile suspension in aqueous vehicle buffered with
dibasic sodium phosphate to pH 7.1 to 7.4
 Isophane Insulin Suspension and
Insulin Injection
- premixed formation of isophane insulin
suspension and insulin suspension and insulin
injection
 Humalog Mix
- manufactured premixed insulin lispro and
neutral protamine lispro (NPL) in fixed ratio
 Insulin Zinc Suspension
 - the smaller amorphous form has most
prompt hypoglycemic action & absorbed
more rapidly than the larger crystalline
form
- contains zinc chloride
 Insulin Glargine
- long-acting basal insulin preparation intended
for once daily subcutaneous administration at
bedtime in the treatment of type I diabetes
melitus in adults and children
- can also be used by adults with type II
diabetes who require long-acting insulin

 Extended Insulin Zinc-Suspension

- sterile suspension of zinc insulin crystals in an
aqueous solution medium buffered with sodium
acetate to pH 7.2 to 2.5
 Insulin Infusion Pumps
- patients achieve and maintain blood glucose to
nearly normal levels on a constant basis

INSULIN PREPARATIONS:
- Expiration date is set after 24 months after
filling
- Amorphous form of zinc chloride added to
insulin prep. Has prompt action than the
crystals
- Freezing is avoided during storage
- Preparations with neutral pH are more stable
than with acidic pH
 SOME INJECTIONS USUALLY PACKAGED AND
ADMINISTERED IN SMALL VOLUME
 Chlorpromazine HCl
- Antipsychotic drug with antiemetic
 Cimetidine HCl
- Histamine H2 antagonist
 Dexamethasone sodium phosphate
- Glucocorticoid
 Digoxin
- Carditonic
 Diphenhydramine HCl
- Ethaqnolamine, nonselective antihistamine
 Furosemide
- Loop diuretic
 Phenytoin sodium
- Anticonvulsant
 Procaine penicillin G
- Anti-infective
 Propranolol HCl
- Beta-adrenergic receptor blocker for
hypertension
 Verapamil HCl
- Calcium channel blocker
 Heparin sodium
- Anticoagulant
 Hydromorphone HCl
- Opioid analgesic
 Lidocaine HCl
- Cardiac depressant
 Meperidine HCl
- Opioid analgesic
 Methoclopramide monohydrochloride
- Gastrointestinal stimulant
 Morphine sulfate
- Opioid analgesic
 Oxytocin
- Oxytocic
Single- dose container
 Hermetic container holding a quantity of sterile drug for
single dose
 When opened cannot be resealed for assurance
sterility is maintained

Multiple- dose container

 Hermetic container permits withdrawal of successive
portions of the contents without changing the strength,
quality or purity of remaining portion
 SOME INTRAVENOUS INFUSIONS
ADMINISTERED IN VOLUMES OF 1 L
OR MORE (ALONE OR WITH OTHER
DRUGS)
 Amino acid
- Fluid and nutrient replenisher
 Dextrose Injection, USP
- Fluid and nutrient replenisher
 Dextrose and Sodium Chloride
Injection, USP
- Fluid, nutrient, electrolyte replenisher
 Mannitol Injection, USP
- Diagnostic aid in renal functions, diuretic, fluid
and nutrient replenisher
 Ringer’s Injection, USP
- Fluid and electrolyte replenisher
 Lactated Ringer’s Injection, USP
- Systemic alkalinizer; fluid and electrolyte
replenisher
 Sodium Chloride Injection, USP
- Fluid and electrolyte replenisher; isotonic
vehicle
 LARGE-VOLUME PARENTERALS
 Maintenance Therapy
 Replacement Therapy
 Water Requirement
 Electolyte Requirement
 Caloric Requirement
 Parenteral Nutrition
 Electrolytes
- Sodium
- Potassium
- Magnesium
- Calcium
- Chloride
- Acetate
- Phosphate
 Enteral Nutrition
 Intravenous Infusion Devices
 SPECIAL CONSIDERATIONS ASSOCIATED
WITH PARENTERAL THERAPY
 Look-alike Products
 Adsorption of Drugs
- Chlorpromazine HCl
- Diazepam
- Insulin
- Nitroglycerin
- Promazine HCl
- Promethazine HCl
- Thiopental sodium
- Thioridazine HCl
- Thrifluoperazine HCl
- Warfarin sodium
 Handling and Disposal of
Chemotherapeutic Agents for Cancer
 OTHER INJECTABLE PRODUCTS:
PALLETS OR IMPLANTS
 Levonorgestrel Implants
- Norplant system
- set of 6 flexible closed capsules of a
dimethylsiloxane-methyl vinyl Siloxane copolymer,
each containing 36 mg of the progestin
- excellent contraceptive
Zoladex implant
- Goserelin acetate implant, Zeneca Pharmaceuticals
– treatment of prostatic cancer
Crinone Gel – assists in reproduction
Lacrisert – for treatment of dry eyes
-
 IRRIGATION AND DIALYSIS SOLUTIONS

- Does not enter into the circulatory system

- Packaged as LVP

 Irrigation Solutions
- intended to bathe or wash wounds, surgical
incisions, or body tissues

 Dialysis Solutions
- separations of substances from one another in
solution by taking advantage of their differing
diffusibility through membranes
 EXAMPLES OF IRRIGATION SOLUTIONS
 Acetic Acid Irrigation, USP
 Neomycin and Polymixin B Sulfates Solution for
Irrigation, USP
 Ringer’s Irrigatio, USP
 Sodium Chloride Irrigation, USP
 Sterile Water for Irrigation USP
Some precautions observed during
manufacture, storage & use of products
to prevent entry of contaminants
 Once opened, ampul cannot be resealed, unused portion
not retained & used (content loss sterility)
 Prime requisite of parenteral soln: clarity
- sparkling clear & free of particulate matter
 During mfture, parenteral soln is filtered before it goes into
the container
 Containers are selected:
- Chemically resistant to the soln
- Highest quality to minimize chances of container
components leaching into the solns
 During container filling – use laminar flow hoods
Some precautions observed during
manufacture, storage & use of products
to prevent entry of contaminants
 Personnel mfg parenterals
- provided with monofilament fabrics (does not lint), face
hoods, caps, gloves & disposable shoe covers to
prevent contamination
 After filling & sealing: visual/automatic inspection for
particulate matter
- clarity : test requirement done to avoid distribution &
use of parenterals that contain particulate matter
END