Vol 4 | Issue 1 | 2014 | 36-41.

e-ISSN 2249 7706

print-ISSN 2249 7714

International Journal of

Advanced Pharmaceutics
www.ijapjournal.com

INJECTABLE PREPARATIONS- AN EMERGING DOSAGE FORMS

M.Jayasree1, C.Sowmya2, L.Divya1, M.Niranjan Babu3, V.Rajasekhar Reddy1,
V.Lavakumar4*
1

Department of Pharmaceutics, Sevenhills College of Pharmacy, Tirupati, Andhra Pradesh, India.

2
Faculty, Department of Pharmaceutics, Omer El Mukhtar University, Al-Beida, Libiya.
3
Principal, Sevenhills College of Pharmacy, Tirupati, Andhra Pradesh, India.
4
Research Director, Sevenhills College of Pharmacy, Tirupati, Andhra Pradesh, India.

ABSTRACT
Injectables occupy a considerable prominence in world market irrespective of diminishing growth in the
pharmaceutical market for 2-3 years. The advancements in technology up-gradation and investments have provided immense
growth opportunities for injectables to emerge in the worldss pharmaceutical industry in recent years. According to RNCOS'
research report, "UK Injectables Market Outlook to 2017", the market is anticipated to grow at a rate of approximately 4.5%
during 2012-2017. The increasing need of injectables for diseases like diabetes, infectious diseases and arthritis is primarily
driving the market. A lot of investment is being done in research and development of injectables in order to improve their
medical outcomes. Here it is worth mentioning that many countries governments have significantly contributed towards the
development of innovative medicines. Certain pharmaceutical firms in world injectable market have established their foothold
given the diverse and innovative product offerings. Several small pharma majors too have been aggressively competing with
big pharmaceutical players in order to establish themselves in the market. This review highlights the basic types of injectable
preparations and their quality control tests with their standards.
Keywords: Injectable Preparations, Powders for Injection, Implants, Sterility Testing.
INTRODUCTION
Injectable Preparations are also called as
parenteral preparations. Injectable preparations are sterile
preparations and are administered by injection, infusion or
implantation [1]. An injection (often referred to as a "shot"
in US English, or a "jab" in UK English) is an infusion
method of putting fluid into the body, usually with a
syringe and a hollow needle which is pierced through the
skin to a sufficient depth for the material to be
administered into the body. An injection follows a
parenteral route of administration; that is, administration
via a route other than through the digestive tract.
There are several methods of injection or infusion
used
in
humans,
including
intradermal,
subcutaneous, intramuscular, intravenous, intraosseous,intr
aperitoneal, intrathecal, epidural, intracardiac, intraarticular
, intracavernous, and intravitreal. Rodents used for research
are often administered intra cerebral and intra cerebro

ventricular injections as well. Long-acting forms of

subcutaneous/intramuscular injections are available for
various drugs, and are called depot injections. Injections
are among the most common health care procedures, with
at
least
16
billion
administered
in developing and transitional countries each year. 95% of
injections are administered in curative care, 3% are
for immunization, and the rest for other purposes, such
as blood transfusions [2]. Approximately 40% of injections
worldwide are administered with unsterilized, reused
syringes and needles, and in some countries this proportion
is 70%, exposing millions of people to infections.
Another risk is poor collection and disposal of
dirty injection equipment, which exposes healthcare
workers and the community to the risk of needle stick
injuries. In some countries, unsafe disposal can lead to resale of used equipment on the black market. Many
countries have legislation or policies that mandate that

Corresponding Author:- Lavakumar V Email:- shcpresearch@gmail.com

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healthcare professionals use a safety syringe (safety
engineered needle) or alternative methods of administering
medicines whenever possible. Open burning of syringes,
which is considered unsafe by the World Health
Organization, is reported by half of the non-industrialized
countries
To improve injection safety, the WHO recommends the
following, [3]
1. Changing the behavior of health care workers and
patients.
2. Ensuring the availability of equipment and supplies.
3. Managing waste safely and appropriately.
Characterization of injectables: [4] Injectables are
characterised for the following tests:
Solubility & Excipient Compatibility
Physiochemical Characterization of API
Hygroscopicity Evaluation
Plasma Compatibility Studies
Aggregation Analysis by SEC (Peptides)
Thermal Characterization
Filter Compatibility Assessment
Adsorption
FORMULATION OF INJECTABLES
Injectable Preparations should be prepared by
methods which ensures the Sterility, avoids contamination
of foreign matters, pyrogens, Micro-organisms and
Bacterial Endotoxins. Water for injection is most
commonly used as vehicle for injectables solutions and
suspensions. Other suitable vehicles may be used provided
they are safe in the volume of injection administered and it
should not interfere with the therapeutic efficacy of
formulation. Other additives like Buffers, Antioxidants,
Chelating agent, Preservatives and stabilizer etc., can be
added to preparations. Colouring agents are not added
solely for colouring purpose of finished product [5-6].
Aqueous
preparations
administered
by
Subcutaneous, Intradermal, IM, IV route are made isotonic
with blood by addition of Sodium Chloride or such suitable
agent. Buffering agents are not used for preparations used
for intraocular or intra cardiac injection or in products that
may gain access to the cerebrospinal fluid. Preservatives
are added in multi dose containers. Preservative should not
be added when the volume to be injected as a single dose
exceeds as 15 ml.
TYPES AND STANDARD TESTS OF INJECTABLES
Each final container of injectable preparation shall be
inspected individually.
There are five main types of injectable preparations:
1. Injections.
2. Powder for injection.
3. Intravenous Infusion.
4. Concentrated solutions for injections.
5. Implants [7-9].

INJECTIONS
Injections are sterile solutions, emulsions or
suspensions prepared by dissolving emulsifying or
suspending the active ingredients and other additives in
water for injection or other suitable non aqueous vehicle or
in mixture of two, if they are miscible [10-11].
Standards
1. Particulate Matter
Comply with limit test for Particular matters.
2. Uniformity of Content
The Preparation being examined complies with
the test if in the total samples of 30 containers not more
than one individual value is outside the limits 85% to
115% and none is out side the limits 75% to 125% of the
average values. This test is not applicable for suspensions
for injection containing Multi-vitamins and Trace
Elements.
3. Extractable Volumes
a) Volume Less than 5ml: The average content of 5
containers is not less than the nominal volume and not
more than 115% of the nominal volumes.
b) Volume more than 5ml: The average content of 3
containers is not less than the nominal volume and not
more than 110% of the nominal volumes.
4. Sterility: Should comply with the test for Sterility
March 2012
5. Pyrogen Test: Comply with the Test for Pyrogen and
Test for Bacterial Endotoxins.
6.
pH:
Comply
with
the
specifications.
7. Weight per ML: Comply with specifications.
8. Leak test for Ampoules: No Leak ampoules observed.
POWDERS FOR INJECTION
Powder for injections are sterile solid substances
(including freeze dried material) which are distributed in
their final containers which, when shaken with the
prescribed volume of the appropriate sterile liquid, rapidly
form clear and practically particle-free solutions or
uniform suspension. Powders for injection (PIs) are a
popular parenteral dosage form for drugs that cannot be
marketed as ready-to-use injectables because of their
instability in an aqueous environment. PIs are relatively
simple with respect to formulation and process
development. However, their performance and stability is
critically affected by a number of parameters [11-12].
Powders for injection (PIs) constitute an
important category of dosage forms for active molecules.
Because of their instability in the aqueous environment,
PIs cannot be marketed as ready-to-use injectables (1).
Instead, they are marketed as dry powders to be
reconstituted with a suitable vehicle just before
administration. The final form after reconstitution may be
either a solution or a suspension (2). Typical molecules in

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this category include beta -lactam antibiotics,
cephalosporins, and acyclovir.
Depending on their formulation strategy, PIs can
be categorized into two classes. Two strategies can be
adopted for the formulation and manufacture of PIs. The
first strategy of lyophilizing (freeze-drying) the primary
pack allows the formulation of drugs that are thermolabile
or unstable in aqueous solution. However, lyophilisation
normally yields an amorphous or partially amorphous
product, which leads to solid-state instability. A morestable crystalline stage can be obtained by crystallization in
aseptic conditions, and it can be maintained by directly
filling the sterile dry-powder drug into pre sterilized vials.
The dry-filling process also is much more cost effective
because it requires fewer infrastructures as well as a
reduced amount of energy and a shorter amount of time to
produce a batch. These reasons have made dry-filled PIs a
popular dosage form. A PI formulation may consist of drug
only or drug plus excipient.
Standards
1. Uniformity of content: as described under injections.
2. Uniformity of Weight: This test is not applicable for
powder for injection that are required to comply with the
test for Uniformity of content of all active ingredients.
Test is complies when, not more than two weight deviate
from the average weight by more than 10% and nondeviates by more than 20% from 20 samples.
3. Sterility test: It should comply with the test for the
sterility.
4. Loss on drying: It should comply with specifications.
INTRAVENOUS INFUSIONS
These are sterile aqueous solutions or emulsions
with water as continuous phase. When a drug is infused
intravenously at a constant rate, a plateau concentration
will be reached progressively in the most frequently most
of the cases follows first order kinetics. On starting the
infusion, there is no drug in the body and therefore, no
elimination. The amount of drug in the body then rises, but
as the drug concentration increases, so does the rate of
elimination. Thus, the rate of elimination will keep rising
until it matches the rate of infusion. The amount of drug in
the body is then constant and is said to have reached a
steady state or plateau.
The factors affecting the steady state plasma drug
concentration are:

plateau is determined by the elimination half-life of the

drug, which results from clearance and volume of
distribution. Thus, the Vd does not influence the steady
state concentration but merely the time required to
approach the plateau. After 4 elimination half-lives the
drug plasma concentration is 93.75% of the steady state
plasma concentration. Likewise, when changing infusion
rates, the time required to reach the new steady state also
depends on the half-life of the drug.They are free from
pyrogens or Bacterial Endotoxins, they are usually made
isotonic with blood and they dont contain any
antimicrobial preservatives.
STANDARDS
1. Particulate Matter
Intravenous infusions that are solutions and supplied in
containers with a nominal content of 100ml or more
comply
with
test
for
particulate
matter.
2. Sterility: Comply with test for sterility.
3. Pyrogen: Comply with test for pyrogens if test for
Bacterial Endotoxin is not prescribed.
4. Assay for Active ingredients: Comply with
specifications.
5. pH: Comply with specifications.
6. Weight per ml: Comply with specifications.
7. Filled / Extractable Volumes: Comply with
specifications.
CONCENTRATED SOLUTIONS FOR INJECTIONS
Concentrated solutions for injections are sterile
solutions that are intended for administration by injection
or by IV infusion only after dilution with suitable dilution
with a suitable liquid. After dilutions these preparations
should comply with the requirements of tests for injection
or intravenous infusions as appropriate.

Infusion rate (Ro)

The steady state drug concentration is
proportional to the infusion rate. Thus, a higher infusion
rate will result in a higher steady state plasma drug
concentration

IMPLANTS
Implants are sterile solid preparations of size and
shape for implantation into body tissues so as to release
active ingredient over an extended period of time.
An implant is a medical device manufactured to replace a
missing biological structure, support a damaged biological
structure, or enhance an existing biological structure.
Medical implants are man-made devices, in contrast to
a transplant, which is a transplanted biomedical tissue. The
surface of implants that contact the body might be made
of a biomedical material such as titanium, silicone
or apatite depending on what is the most functional. In
some cases implants contain electronics e.g. artificial
pacemaker and cochlear
implants.
Some
implants
are bioactive, such as subcutaneous drug delivery devices
in the form of implantable pills or drug-eluting stents [1416].

Clearance
Higher clearance of the drug will result in lower
plasma drug concentration at plateau.The time to reach the

Standards
1. Sterility: Comply with test for sterility.
2. Assay content of active ingredients: Comply with

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specifications.
3. Average Weight of implants: Comply with
specifications.
4. Rate of Release (Dissolution test): Comply with
designed period of release.
5.
Hardness:
Comply
with
specifications.
6. Other tests: As specified in monograph
Classification of Parenteral Preparation based on
Preparation:
Parenteral solutions are packaged as large volume
parenteral (LVP) solutions and small volume parenteral
(SVP) solutions
1. Small Volume Parenterals (SVPs): The USP
designation small-volume injection applies to an injection
packaged in containers labeled as containing 100 mL or
less.
2. Large Volume Parenterals (LVPs): LVP solutions are
typically bags or bottles containing larger volumes of
intravenous solutions. Common uses of LVP solutions
without additives include: 1) correction of electrolyte and
fluid balance disturbances; 2) nutrition; and Vehicle for
administering other drugs. Large volume parenteral
solutions are packaged in containers holding 100 ml or
more. There are three types of containers: glass bottle with
an air vent tube, glass bottle without an air vent tube, and
plastic bags.
QUALITY CONTROL TESTING OF INJECTABLE
PEPARATIONS
The quality of injectables is the sum of all
parameters that contribute to safety and therapeutic
efficacy of the drug.
The USP compendial
requirements
has
recommended the following tests for injectable products
[17]
1. Weight variation or content uniformity
2. Particulate matter in injections
3. Bacterial endotoxin test
4. Pyrogen test
5. Sterility test
Weight variation or content uniformity test
This test is intended for sterile solids used for
parenteral preparation. The weight of 10 individual sterile
units is noted and the content is removed from them and
empty individual sterile unit is weighed intern. Then net
weight is calculated by subtracting empty sterile unit
weight form gross weight. The content of active ingredient
in each sterile unit is calculated by performing the assay
according to the individual monographs. The content in 10
sterile units is calculated by performing the assay. The
dose uniformity is meet if the amount of active ingredient
is within the range of 85-115.0% of label claim as
determine by the content uniformity method or weight

variation method. The dose uniformity is also meet if the

potency value is 100% in the individual monograph or less
of label claim multiplied by average of limits specified for
potency in individual monograph divided by 100 provided
that the relative standard deviation in both the cases is
equal to or less than 6.0%. If one unit is outside the range
of 85-115.0%, and none of the sterile unit is outside the
range of 75-125.0% and if the relative standard deviation
of the resultant is greater than 6.0% then, the fore
mentioned test is carried for 20 more sterile units. The
sterile units meet the requirements if not more than one
unit is outside the range of 85-115%, no unit is outside the
range of 75-125.0% and the calculated relative standard
deviation is NMT 7.8%.
Particulate matter in injections
The preparations intended for parenteral use
should be free from particulate matter and should be clear
when inspected visually. Two methods are described
by USP according to the filled volume of the product to be
tested.
For large volume parenterals (LVP's), a filtration
followed by microscopical examination procedure is used.
For small volume parenterals (SVP's) a light obscuration
based sensor containing electronic liquid-borne particle
counter system is used.The USP standards are met if the
LVP's under test contain NMT 50 particles per ml of 10
m, and NMT 5 particles per ml of 25m in an effective
linear dimensional fashion. The USP standards are met if
the SVP's under test contain NMT 10,000 particles per
container of 10 m, and NMT 1000 particles per container
of 25m in an effective spherical diameter [18].
Bacterial Endotoxin test
LAL (Limulus Amebocyte Lysate) test is used to
characterize the bacterial endotoxin that may be present.
The USP reference standard contains 10,000 USP
endotoxins per vial. The LAL reagent is used for gel-clot
formation. The test is performed using stated amounts of
volumes of products, standard, positive control, negative
control of endotoxin. The tubes are incubated at 371C
FOR 60 2 minutes. When the tubes are inverted at 180C
angle, formation of firm gel confirms positive reaction.
While formation of a viscous gel that doesn't maintain its
integrity or absence of a firm gel confirms negative
reaction. The test is invalid if the standard endotoxin or
positive product control doesn't show end point within 1.
Two fold dilution from label claim sensitivity of LAL
reagent or if the negative control shows gel-clot end point
[19].
Pyrogen test
It is performed by using rabbits as test animals.
Initially 10 ml/kg body weight of an animal is injected
through rat vein at 372C within ten minutes from start of
administration. The temperatures are recorded at 1, 2 and 3
hours after injection. The requirements of USP are met if

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1.
2.
3.
4.
5.

Table 1. Marketed Injectables [22]

Marketed Preparation
Therapeutic Benefit
Lupron
depot
PLA Prostate
cancer,
Leuprolide Acetate
endometriosis
Nutropin
depot
PLGA Growth deficiencies
Human growth Hormone
Sandosatin depot PLGA- Acromegaly
glucose Octreotide
Zoladex PLA Goserelin Prostate
cancer,
acetate
Endometriosis
Trelstar
depot
PLGA Prostate cancer
Triptorelin Pamoate
the rise in temperature of individual rabbit is NMT 0.6C
and the sum of rise in temperature of three rabbits is NMT
1.4C. If anyone rabbit shows a rise in temperature of
0.6C and sum of rise in temperature of three rabbits
exceeds 1.4C then the test is repeated using 5 rabbits. The
requirements are met if 3 out of 8 rabbits shows an
individual rise in temperature of NMT 0.6C and sum of
maximum rise in temperature of 8 rabbits is NMT 3.7C
[20].

Sterility Test
Growth promotion medium and incubation
conditions are selected based on the test microorganism.
The sterility test is done using direct transfer and
membrane filtration techniques. Membrane filtration
technique is suitable for liquids, soluble powders with
bacterio static or fungi static properties, oils, creams and
ointments. Sterility test by direct transfer is performed by
aseptic transfer of specified volume from test container to
culture medium and incubated for 14 days and visual
observation of medium is done on 3rd, 4th, 5th, 7th,
8th and 14th day. A membrane filter with porosity of
0.45m with diameter of 47mm with flow rate of 55-75 ml
of water per minute at a pressure of 70 cm of mercury
should be used. The test meets the requirements when no
growth is observed and if growth is observed then the test
is repeated in the second stage and generally second stage
is repeated with double the number of specimens tested in
first stage when the test was found to be conducted under
faulty or inadequate aseptic techniques [21].

REFERENCES
1. Gregory AB, Satya SM, Jie L, Judy E. Parenteral dosage forms. Separation Science and Technology, 3, 2001, 269-305.
2. Injection safety. Health Topics A to Z. World Health Organization. 2011.
3. Injection Safety, First do no harm. Advocacy brochure. World Health Organization. 2011.
4. Shayne CG, Christopher PC. Safety Considerations for the administration of Agents by the Parenteral Routes, Acute
Toxicology Testing. 2nd ed, 1998, 197-220.
5. Jess D, Oren F. Injectables and Fillers in Male Patients,Facial Plastic Surgery Clinics of North America. 16(3), 2008, 345355.
6. William R. Shek, Quality Control Testing of Biologics, The Mouse in Biomedical Research, 2nd ed, Volume
III, 2007, 731-757.
7. Joseph MD. Latex-free drug vials and injectables encouraged, Journal of Emergency Nursing, 24(1), 1998, 8.
8. Sciarra JJ. Discussion Meeting contraceptive needs worldwide: the role of monthly combined injectables. International
Journal of Gynecology & Obstetrics, 62(Supplement 1), 1998, S41-S42.
9. David AFE, Ara SM, Deron JB. Survey of future injectables, Facial Plastic Surgery Clinics of North America,
10(2), 2002, 199-204.
10. Hansen HC, McKenzie-Brown AM, Cohen SP, Swicegood JR, Colson JD & Manchikanti L. Sacroiliac joint
interventions: a systematic review. Pain Physician, 10(1), 2007, 165.
11. Carette S, Leclaire R, Marcoux S, Morin F, Blaise GA, St.-Pierre A & Blanchette C. Epidural corticosteroid injections for
sciatica due to herniated nucleus pulposus. New England Journal of Medicine, 336(23), 1997, 1634-1640.
12. Boylan JC and Fites AL. Parenteral Products, in Modern Pharmaceutics, Banker GL and Rhodes CT, Eds. (Marcel
Dekker Inc., Newyork, NY, 1979, 445.
13. DeLuca PP and Boylan JC. Formulation of Small-Volume Parenterals in Pharmaceutical Dosage Forms: Parenteral
Medications, 1, Avis KE et al., Eds. Marcel Dekker Inc., New York, NY, 1992, 215.
14. Charles VT, Tong-Mei W, Sean H, Amy JCT. Constructing a dental implant ontology for domain specific clustering
and life span analysis. Advanced Engineering Informatics, 27(3), 2013, 346-357.
15. Julie B, Virginie F, Anne-Sophie B, Fabrice L, Cyrille H. A life-threatening ectopic pregnancy with etonogestrel implant.
Contraception, 85(2), 2012, 215-217.
16. Albrektsson T, Zarb G, Worthington P & Eriksson AR. The long-term efficacy of currently used dental implants: a review
and proposed criteria of success. Int J Oral Maxillofac Implants, 1(1), 1986, 11-25.
17. Hanna SA. Quality Assurance. In: Avis KE, Lieberman HA, Lachman L, editors. Pharmaceutical dosage forms: Parenteral
Medications. 2nd ed, Marcel Dekker, Newyork. 1, 1996, 1-65.
18. United states pharmacopoeia, USP29 NF24, 31st edition, particulate matter testing in injections, 2722.
19. United states pharmacopoeia, USP29 NF24, 31st edition, test for bacterial endotoxins in injections, 2521.

40 | P a g e

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20. United states pharmacopoeia, USP29 NF24, 31st edition, pyrogen testing of sterile preparations, 2546.
21. United states pharmacopoeia, USP29 NF24, 31st edition, sterility testing of parenterals, 2508.
22. Doc QAS/11.413 FINAL, 2011, world health organisation.

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