Sterile Dosage Forms and

Delivery Systems
PARENTERALS
By
Alexander David F. Famadulan
Jayvee Abeia

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.
!NJE"T!#NS

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, stabili"er, antibacterial
preservative, antio#idant
- packaged in hermetic containers

Pyrogens
- fever-producing organic substances arising from
microbial contamination
- responsible for many of the febrile
reactions in patients following $%
injections.
D!FF. PARENTERAL R#%TES
AD&!N!STRAT!#N
Drugs may be in'eted into t(e almost any
organ or area o) t(e body$

joints (intra-articular)

joint fluid area (intrasynovial)

spinal column (intraspinal)

spinal fluid (intrathecal)

arteries (intra-arterial)

heart (intracardiac)

vein intravenous, $%!

muscle (intra-muscular, IM)

skin (intradermal, ID, intracutaneous)

under the skin (subcutaneous, S, sub-!, S!,

hypodermic, hypo)
!NTRA*EN#%S R#%TE
!NTR*EN#%S R#%TE

Thrombus and embolus )ormation

- main ha"ard of $% 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.
- "ptimum 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+disin)eted$
&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 )or intravenous )luids

- adjusted according to the needs of patient
- e#pressed in m'/hour and range from ()
to *+, m'/hour.

Intravenous drugs
- in a-ueous solution
- must mi# with the circulating blood and not
precipitate from solution: lead to pulmonary
microcapillary occlusion and bloc#age of blood
flow.

Intravenous fat emulsions

- use: source of calories and essential fatty
acids for patients re-uiring parenteral nutrition
for e#tended periods.

Patientcontrolled analgesia !P"A#

- controls pain surgical procedures, labor, sickle
cell crisis, and cancer!, with less side effects
- minimi"es variations bet. suboptimal pain
relief & overuse of opioids
AD*ANTA,ES$
- 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
!NTRA&%S"%LAR R#%TE

!ntramusular in'etions o) drugs

- oleaginous sus.ension an only be administered
t(roug( t(is route
- effects are less rapid but longer lasting than $%
administration.
- performed deep into the skeletal muscles

!n'uries to .atients 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
!NTRA&%S"%LAR R#%TE

)re/uently used site

- adults
&upper outer -uadrant of the gluteus
ma#imus
- in)ants and young (ildren
& deltoid muscles of the upper arm/midlateral
muscles of the thigh

volume of medication administered :

- + m' in the gluteal region
- ) m' in the deltoid of the arm.

$trac% injection techni&ue for I'

- stain upper tissue by sealing medications in
the lower muscle
- creates a . pattern that blocks infiltration of
medication into the subcutaneous tissue
- injection is ) to / inches deep, and ),-gauge
and ))-gauge needle is used.
S%B"%TANE#%S R#%TE

0se: for injection of small amounts of

medication.

0sual route for insulin injection

$njection beneath the skin

- in the loose interstitial tissue of the outer,
upper arm, the anterior thigh, or the lower
abdomen.

ma#imum amount of medication injected

- *./ m',
&greater than ) m' will most likely cause
painful pressure.
S%B"%TANE#%S R#%TE
S%B"%TANE#%S R#%TE

Syringes used
- up to / m' capacities and )(-gauge to
)1-gauge needles are.

!rritating drugs and t(ose in t(i0

sus.ension
- produce indurations, sloughing, or
abscess and may be painful
!NTRADER&AL R#%TE

in'eted into the corium, the more vascular

layer of the skin just beneath the epidermis.

substanes inlude
- various agents for diagnostic determinations,
desensiti"ation, or immuni"ation.

site )or intradermal in'etion

-anterior forearm.

needle em.loyed
- short three-eights of an inch! and narrow )/-
gauge to )1 gauge!
!NTRADER&AL R#%TE
!NTRADER&AL R#%TE
#F!"!AL T1PES #F !NJE"T!#NS

Injection
-li-uid preparations that are drug substances or
solutions

(or Injection
-dry solids 2 suitable vehicles solutions
conforming to the re-uirements for injections

Injectable Emulsion
-li-uid preparation of drug substance dissolved or
dispersed in a suitable emulsion medium

Injectable suspension
-li-uid preparation of solid suspended in a suitable
li-uid medium

(or Injectable Suspension

-dry solid 2 suitable vehicle preparation
conforming to the re-uirements for injectable
suspensions
Di))erenes .arenteral .roduts 2
Di))erenes .arenteral .roduts 2
ot(er dosage )orms
ot(er dosage )orms

3olvents/vehicles
- meet special purity & other standards
ensuring their safety by injection

restricted in certain parenteral products: use of

added subs4s buffers, stabili"ers & antimicrobial
preservatives!

5arenterals:
- always sterili"ed
- meet the compendial standards for particulate
matter
- packaged in special hermetic containers of
special & high -uality
Di))erenes .arenteral .roduts 2
Di))erenes .arenteral .roduts 2
ot(er dosage )orms
ot(er dosage )orms

6ach injection container

- filled slightly in e#cess 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

3pecific labeling regulations apply to injections

3terile powders intended for

solution/suspensions immediately prior to
injection
- packaged as free"e-dried powders to permit
ease of soln/suspension upon the addition of the
solvent/vehicle
S#L*ENTS AND *E3!"LES F#R !NJE"T!#NS

)ater for Injection* +SP

- most fre-uently used solvent in the large scale
manufacturer of injections
- .uri)ied by distillation or by reverse
osmosis and meets the same standards for
presence of total solids
- use$ manufacture of injectable products to be
sterili"ed after preparation.

Purified )ater* +SP

- not more than * mg/*,, m' $ater for
Injection

Sterile )ater for Injection* +SP

- may contain slightly more total solids than
$ater for Injection because of the leaching of
solids from the glass-lined tanks during
sterili"ation
- use: solvent or diluent for already sterili"ed
and packaged injectable medication.

,acteriostatic )ater for Injection* +SP

- sterile water for injection containing one or
more suitable antimicrobial agents.
- 7not intended for neonates8
- use: only in parenterals administered in small
volumes because of the presence of
antimicrobial agents

Sodium "hloride Injection* +SP

- sterile isotonic solution of 9a:l in water for injection
- use: &sterile vehicle in solutions or
suspensions of drugs for parenteral
administration
&at(eter or intravenous line to
in)use )luids 2 mediations
to maintain .oteny

,acteriostatic Sodium "hloride Injection

- sterile isotonic solution of 9a:l in water
for injection
- 0se: &for bacteriostatic water for
injection
&catheter or intravenous line flush
to maintain potency

-inger.s Injection* +SP

- sterile solutions of 9a:l, ;:l, and :a:l
)
in water for injection
- use: vehicle for other drugs/ alone as an
electrolyte replenisher and plasma volume
e#pander

/actated -inger.s Injection

- contains 9a:l, ;:l, :a:l
)
& 9a lactate
- fluid and electrolyte replenisher
and a systemic alkaly"er
N#NA4%E#%S *E3!"LES
- use: when physical or chemical factors limit the
use of a wholly a-ueous vehicle
<ualities:
- nonirritating, nonto#ic, and not sensiti"ing
- must not e#ert a pharmacologic activity of its
own, nor affect the activity of the medicinal agent
- physical and chemical properties evaluated and
determined:
stability at various p= levels, viscosity,
fluidity, boiling point, miscibility with body
fluids, low vapor pressure and constant
purity.
ADDED S%BSTAN"ES in in'etions

035 permits addition of suitable substanes$

antibaterial .reservatives5 bu))ers5
solubili6ers5 antioxidants5 and ot(er
ad'unts.
- 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.

&ET3#DS #F STER!L!7AT!#N
Sterili0ation
- destruction of all living organisms and their spores
or their complete removal from the preparation.

Steam Sterili0ation
- conducted in an autoclave and employs steam
under pressure
- microbial destruction is caused by denaturation &
coagulation of bacterial proteins by moist heat
- Baillus stearot(ermo.(ilus: biological
indicator
- applicable to pharmaceutical preparations and
materials:
&withstand the re-uired temperatures
&penetrated but not adversely affected by
moisture

Dry 1eat Sterili0ation

- carried out in ovens, heated by gas or electricity
and are generally thermostatically controlled
- Baillus subtilis: biological indicator
- use: for substances not effectively sterili"ed by
moist heat

Sterili0ation by (iltration
- depends on the physical removal of
microorganisms by adsorption on the filter medium
or by a sieving mechanism
- use: for heat-sensitive solutions
'illipore filter
- thin plastic membrane of cellulosic esters with
millions of pores per s-uare inch
Baterial Filtration
Baterial Filtration
- >est suited for e#temporaneous preparation of sterile
solution
advantages
-
speed in the filtration of small -uantities of solution
-
ability to sterili"e thermolabile materials
-
relatively ine#pensive e-uipment re-uired
-
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,
sterili"ation, or use!.

2as Sterili0ation
- re-uires speciali"ed e-uipment resembling an
autoclave, and many combination steam
autoclaves and ethylene o#ide sterili"ers
- for sterili"ing heat resistant & moisture
resistant products

Sterili0ation by Ioni0ation -adiation

- sterili"ation by gamma rays and by cathode

rays, but application of such techni-ues is
limited because of the highly speciali"ed
e-uipment re-uired and the effects of
irradiation on products and their containers
- biological indicator: Baillus .umilus
*AL!DAT!#N #F STER!L!T1
- effectiveness of thermal sterili"ation -uantified:
&determination & calculation of ? value to e#press
thermal death.
,iologic Indicator
best used to validate sterility for steam
sterili0ation
- a characteri"ed preparation of specific
microorganisms resistant to a particular
sterili"ation process
- use: to monitor a sterili"ation cycle and/or
periodically to revalidate the process

Thermal Death Time

- time re-uired to kill a particular organism under
specified conditions
P1R#,ENS

ausative material o) .yrogens

- a lipopolysaccharide from the outer cell wall
of the bacteria and endoto#ins.
- material is thermostable and water soluble
remain in water even after sterili"ation by
autoclaving or by bacterial filtration!.

ommon means o) removing .yrogens

- by o#idi"ing: easily eliminate gases or
nonvolatile salts of any acidic compounds
present.
Pyrogen Test5 %SP

0ses: healthy rabbits properly maintained in

terms of environment and diet before the test

9ormal, 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 *@: from each other
Exam.les o) sterile drugs .re.ared
and .a0aged 8it(out
.(armaeutial additives 9bu))ers5
.reservatives5 stabili6ers5 and
toniity agents:$

%mpicillin sodium

efti&o'ime sodium

efta&idime sodium

efuro'ime sodium

(anamycin sulfate

)afcillin sodium

*enicillin + ben&athine

Streptomycin sulfate

,obramycin sulfate
Sterile drugs )ormulated 8it(
.(armaeutial additives and
intended to be reonstituted .rior to
in'etion$

yclophosphamide

Dactinomycin

-ryhtromycin lactobionate

.ydrocortisone sodium succinate

Mitomycin

)afcillin sodium

"'ytetracycline hydrochloride

*enicillin + potassium

/inblastine sulfate
!nnovations done )or .o8ders )or
!nnovations done )or .o8ders )or
reonstitution
reonstitution

3ometimes a li-uid is packaged along

with the dry powder

Ary powders are packaged in containers

large enough to permit proper shaking
with the li-uid component

Bi#-C-vial
- incorporates the $% systems that allow
preparing small volumes infusions
e#temporaneously

Dbbott DAA-%antage 3ystem $%5>

&onovial Sa)ety ,uard
&onovial Sa)ety ,uard

Banufacturer: >ecton Aickinson

5harmaceutical 3ystems

9ew $% system for use in preparing

e#temporaneous small-volume infusions
using plastic minibags

3aves time, uses fewer materials & costs

less

$ntegrated drug transfer with a protective

shield surrounding the attached transfer
needle
PA";A,!N,5 LABEL!N,5 AND
ST#RA,E #F !NJE"T!#NS

Singledose container
- hermetic container for parenteral
administration as a single dose
- when opened, cannot be resealed with
assurance that sterility has been maintained

'ultipledose container
- hermetic container that permits withdrawal of
successive portions of the contents without
changing the strength, -uality, or purity of the
remaining portion
AS3P R!S; LE*EL "LASS!F!"AT!#N #F
P3AR&A"1-PREPARED STER!LE
PR#D%"TS
-is% /evel 3
<. Produts

Stored at$
- room temperature and administered within
)E hours of preparation
- under refrigerator for F days or less before
complete administration over a period not to
e#ceed to )( hours

?ro"en for /, days or less before complete

administration
AS3P R!S; LE*EL "LASS!F!"AT!#N #F
P3AR&A"1-PREPARED STER!LE
PR#D%"TS
-is% /evel 3
=. 0npreserved sterile products for administration
to one patient or batch-prepared products
- containing suitable preservatives for
administration to more than one patient
/. 5roducts prepared by closed-system aseptic
transfer of sterile nonpyrogenic finished
pharmaceutics obtained from licensed
manufacturer into sterile final containers
obtained from licensed manufacturer
AS3P R!S; LE*EL "LASS!F!"AT!#N #F
P3AR&A"1-PREPARED STER!LE PR#D%"TS
-is% /evel 4
Produts $

stored beyond F days under refrigeration/stored

beyond /, days fro"en or administered beyond
)E hours after preparation and storage at room
temperature

>atch-prepared without preservatives for use

by more than one patient.

compounded by comple# 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
AS3P R!S; LE*EL "LASS!F!"AT!#N #F
P3AR&A"1-PREPARED STER!LE PR#D%"TS
-is% /evel 5
Produts$

compounded from nonsterile ingredients or

compounded with nonsterile compounds with
nonsterile components, containers, or
e-uipment before terminal sterili"ation

prepared by combining multiple ingredients by

using an open-system transfer or open reservoir
before terminal sterili"ation.
"R!TER!A !N DETER&!N!N, T3E
PR#D%"T>S T!TLE F#R ESTABL!S3ED
NA&ES #F !NJE"TABLE PR#D%T"S
a. Li/uids

6Drug7Injection
- title for li-uid preparations that are drug
substances or solutions thereof

6Drug7Injectable suspension
- title for li-uid preparations of solids suspended
in a suitable li-uid medium

6Drug7Injectable emulsions
- title for li-uid preparations of drug substances
dissolved or dispersed in suitable emulsion
medium
b. Solids

6Drug7(or injection
- dry solids 2 suitable vehicles solutions
conforming in all respects to the re-uirements
for injections

6Drug7(or injectable suspension

- dry solids that 2 suitable vehicles
preparations conforming to the
re-uirements for $njectable 3uspensions
S&ALL-*#L%&E PARENTERALS

Insulin Injection !regular#

-sterile a-ueous 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

1uman Insulin
- produced by using a special non-diseases-
forming laboratory strain of 6. coli and
recombinant A9D technology

/ispro Insulin Solution

- consists of "inc insulin lispro crystals dissolved in a
clear a-ueous fluid
- reated 8(en t(e amino aids at .ositions =?
and =@ on t(e insulin B-(ain are reversed

Insulin %spart
- recombinant ultra-short acting insulin using
Saccharomyces cerevisiae (ba#er0s yeast) as the
production organism

Isophane Insulin Suspension !8P19neutral

protamine hagedorn Insulin#

protamine is added
- sterile suspension in a-ueous vehicle buffered with
dibasic sodium phosphate to p= F.* to F.(

Isophane Insulin Suspension and

Insulin Injection
- premi#ed formation of isophane insulin
suspension and insulin suspension and insulin
injection

1umalog 'i:
- manufactured premi#ed insulin lispro and
neutral protamine lispro 95'! in fi#ed ratio

Insulin $inc Suspension

the smaller amorphous form has most

prompt hypoglycemic action ; absorbed
more rapidly than the larger crystalline
form
- contains "inc chloride

Insulin 2largine
- long-acting basal insulin preparation intended
for once daily subcutaneous administration at
bedtime in the treatment of type $ diabetes
melitus in adults and children
- can also be used by adults with type $$
diabetes who re-uire long-acting insulin

E:tended Insulin $incSuspension

- sterile suspension of "inc insulin crystals in an
a-ueous solution medium buffered with sodium
acetate to p= F.) to ).+

Insulin Infusion Pumps

- patients achieve and maintain blood glucose to
nearly normal levels on a constant basis
!NS%L!N PREPARAT!#NS$
-
6#piration date is set after )( months after
filling
-
Dmorphous form of "inc chloride added to
insulin prep. =as prompt action than the
crystals
-
?ree"ing is avoided during storage
-
5reparations with neutral p= are more stable
than with acidic p=
S#&E !NJE"T!#NS %S%ALL1 PA";A,ED A8D
AD'I8ISTE-ED I8 S'A// <=/+'E

"hlorproma0ine 1"l
- Dntipsychotic drug with antiemetic

"imetidine 1"l
- =istamine =) antagonist

De:amethasone sodium phosphate

- Glucocorticoid

Digo:in
- :arditonic

Diphenhydramine 1"l
- 6tha-nolamine, nonselective antihistamine

(urosemide
- 'oop diuretic

Phenytoin sodium
- Dnticonvulsant

Procaine penicillin 2
- Dnti-infective

Propranolol 1"l
- >eta-adrenergic receptor blocker for
hypertension

<erapamil 1"l
- :alcium channel blocker

1eparin sodium
- Dnticoagulant

1ydromorphone 1"l
- Cpioid analgesic

/idocaine 1"l
- :ardiac depressant

'eperidine 1"l
- Cpioid analgesic

'ethoclopramide
monohydrochloride
- ,astrointestinal stimulant

'orphine sulfate
- Cpioid analgesic

=:ytocin
- C#ytocic
3ingle- dose container

=ermetic container holding a -uantity of sterile

drug for single dose

Ghen opened cannot be resealed for assurance

sterility is maintained
Bultiple- dose container

=ermetic container permits withdrawal of

successive portions of the contents without
changing the strength, -uality or purity of
remaining portion
S#&E !NTRA*EN#%S !NF%S!#NS
AD&!N!STERED !N *#L%&ES #F < L
#R &#RE 9AL#NE #R A!T3 #T3ER
DR%,S:

Amino aid
- ?luid and nutrient replenisher

De:trose Injection* +SP

- ?luid and nutrient replenisher

De:trose and Sodium "hloride

Injection* +SP
- ?luid, nutrient, electrolyte replenisher

'annitol Injection* +SP

- Aiagnostic aid in renal functions, diuretic, fluid
and nutrient replenisher

-inger.s Injection* +SP

- ?luid and electrolyte replenisher

/actated -inger.s Injection* +SP

- 3ystemic alkalini"erH fluid and electrolyte
replenisher

Sodium "hloride Injection* +SP

- ?luid and electrolyte replenisherH isotonic
vehicle
LAR,E-*#L%&E PARENTERALS

'aintenance Therapy

-eplacement Therapy

)ater -e&uirement

Electolyte -e&uirement

"aloric -e&uirement

Parenteral 8utrition
I -lectrolytes
- 3odium
- 5otassium
- Bagnesium
- :alcium
- :hloride
- Dcetate
- 5hosphate

Enteral 8utrition

Intravenous Infusion Devices

SPE"!AL "#NS!DERAT!#NS ASS#"!ATED
A!T3 PARENTERAL T3ERAP1

/oo%ali%e Products

Adsorption of Drugs
- :hlorproma"ine =:l
- Aia"epam
- $nsulin
- 9itroglycerin
- 5roma"ine =:l
- 5rometha"ine =:l
- Jhiopental sodium
- Jhiorida"ine =:l
- Jhrifluopera"ine =:l
- Garfarin sodium

1andling and Disposal of

"hemotherapeutic Agents for "ancer
#T3ER !NJE"TABLE PR#D%"TS$
PALLETS #R !&PLANTS

Levonorgestrel !m.lants
- 9orplant system
- set of 1 fle#ible closed capsules of a
dimethylsilo#ane-methyl vinyl 3ilo#ane copolymer,
each containing /1 mg of the progestin
- e#cellent contraceptive
.olade# implant
- Goserelin acetate implant, .eneca 5harmaceuticals
K treatment of prostatic cancer
:rinone Gel K assists in reproduction
'acrisert K for treatment of dry eyes
-
!RR!,AT!#N AND D!AL1S!S S#L%T!#NS
-
Does not enter into t(e irulatory system
-
Pa0aged as L*P

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
EBA&PLES #F !RR!,AT!#N S#L%T!#NS

%cetic %cid Irrigation, 1S*

)eomycin and *olymi'in 2 Sulfates Solution for

Irrigation, 1S*

3inger0s Irrigatio, 1S*

Sodium hloride Irrigation, 1S*

Sterile $ater for Irrigation 1S*

Some .reautions observed during
Some .reautions observed during
manu)ature5 storage 2 use o) .roduts
manu)ature5 storage 2 use o) .roduts
to .revent entry o) ontaminants
to .revent entry o) ontaminants

Cnce opened, ampul cannot be resealed, unused

portion not retained & used content loss sterility!

5rime re-uisite of parenteral soln: clarity

- sparkling clear & free of particulate matter

Auring mfture, parenteral soln is filtered before it

goes into the container

:ontainers are selected:

-
:hemically resistant to the soln
-
=ighest -uality to minimi"e chances of container
components leaching into the solns

Auring container filling K use laminar flow hoods

Some .reautions observed during
Some .reautions observed during
manu)ature5 storage 2 use o) .roduts
manu)ature5 storage 2 use o) .roduts
to .revent entry o) ontaminants
to .revent entry o) ontaminants

5ersonnel mfg parenterals

- provided with monofilament fabrics does not
lint!, face hoods, caps, gloves & disposable shoe
covers to prevent contamination

Dfter filling & sealing: visual/automatic inspection

for particulate matter
- clarity : test re-uirement done to avoid
distribution & use of parenterals that contain
particulate matter
E N D
E N D