Parenterals, most useful presentation for GPAT aspirant and UG PG students of Pharmacy field. Details regarding parenteral routes, formulation consideration and quality control tests

1. RAJARSHI COLLEGE OF PHARMACY,
BULDANA
Dr. Subhash Deshmane
Asso. Professor

2. Introduction
• Para: outside , Enteron: intestine
• Drugs applied topically to the eye, ear & skin or even
inhaled may be broadly interpreted as parenterals.
• Parenteral products are injected through the skin or
mucous membranes into the internal body
compartments. These are the preparations which are
given other than oral routes.
• According to USP : “ an injection that is packaged in
containers labeled as containing 100 ml or less ”

3. Necessities/Ideal requirement
• Sterility (must) ,
• Pyrogen free (must) ,
• Free from particulate matter (must, )
• Clarity (must),
• Stability (must),
• Isotonicity (should),
• Solvents or vehicles used must meet special purity and other
standards.
• Restrictions on buffers, stabilizers, antimicrobial preservative.
• Do not use coloring agents.
• Must be prepared under aseptic conditions.
• Specific and high quality packaging.

4. ADVANTAGES
• Quick onset of action
• Suitable for the drugs which are not administered by
oral route
• Useful for unconscious or vomiting patients.
• Useful for patients who cannot take drugs orally
• Useful for emergency situations
• Duration of action can be prolonged by modifying
formulation.
• Can be done in hospitals, ambulatory infusion
centers, and home health care

5. DISADVANTAGES
• Pain on injection.
• Difficult to reverse an administered drug’s effects.
• Sensitivity or allergic reaction at the site of injection.
• Requires strict control of sterility & non pyrogenicity
than other formulation.
• Only trained person is required
• Require specialized equipment, devices, and
techniques to prepare and administer drugs.
• More expensive and costly to produce.

6. Routes of Parenteral Administration
Three primary routes of parenteral administration are
commonly employed :
 Subcutaneous
 Intramuscular
 Intravenous
 Other routes : Intra – arterial, Intrathecal,
Intraepidural, Intracisternal, Intraarticular,
Intracardial, Intrapleural, and Intradermal

7. • Intravenous (IV) - vein Routes of administration: 1
to 1000 ml 1 inch ,19 to 20 gauge needle with
injection rate 1ml/ 10 sec. for volume upto 5 ml & 1
ml/ 20 sec. for volume more than 5 ml.
Given: Aqueous solutions Hydro alcoholic solutions Emulsions
Liposome
• IV infusion of large volume fluids (100- 1000 ml)
has become increasingly popular. This technique is
called as Venoclysis . This is used to supply
electrolytes & nutrients to restore blood volume & to
prevent tissue dehydration.

8. • Intramuscular (IM) – Striated muscle fibre 0.5 to 2
ml sometimes upto 4 ml 1 to 1.5 inch & 19 to 22
gauge needle is used Preferably isotonic Principle
sites: Gluteal (buttocks) Deltoid (upper arms) Vastus
lateralis (lateral thigh)
– Given : Solutions Emulsions Oils Suspension
• Subcutaneous (SC) - connective & adipose tissue
under the skin Slower onset than IM Technically
simpler ↓ discomfort & ↓ risk of complications than
IM < 2 mL Narrow control of pH and tonicity
Solutions, suspensions & emulsions Drugs ineffective
orally - insulin, vaccines

9. • Intradermal (ID) – between layers of skin Also
called as diagnostic testing 0.05 ml ½ inch, 25 to 26
gauge needle Should be isotonic
– Given: Diagnostic agents
• Intraspinal (various sub-types) Directly into
cerebrospinal fluid Intra-arterial Usually requires
surgery to expose the artery Intra-articular Directly
into joint Intrasynovial Joint fluid area Intracardiac
…… i.e. Anywhere that you can put a needle.

10. • Intra-arterial (IA): Direct into the artery 2 to 20 ml 20 to
22 gauge Solutions & emulsions can be administered
Given: Radio opaque media Antineoplastic Antibiotics
• Intrathecal: Also called intra-spinal directly given into the
spinal cord 1 to 4 ml 24 to 28 gauge Must be isotonic
– Given: Analgesics Neuroleptics
• Intraarticular : Given directly into the joints 2 to 20 ml 5
inch 22 gauge Must be isotonic
– Given: Morphine Steroids NSAID’s Antibiotics
• Intrapleural : Given directly into the pleural cavity or
lung Used for fluid withdrawal 2 to 30 ml 2 to 5 inch, 16
to 22 gauge needle
– Given: Narcotics Chemotherapeutic agents

11. • Intracardial : Directly given into the heart 0.2 to 1
ml 5 inch , 22 gauge needle Given: Cadiotonics
Calcium salts as a calcium channel blockers

12. Formulation
• Water For Injection(WFI) USP : Highly purified
water used as a vehicle for injectable preparations
which will be subsequently sterilized.
– USP requirement include not more than 10 PPM of total
solids.
– pH of 5.0 to 7.0 WFI may prepared by either distillation or
reverse osmosis.
– Stored for less than 24hr at RT or for longer times at
specific temperatures.
– Should be meet USP pyrogen test It may not contain any
added substances. Stored in chemically resistant tank.

13. • Bacteriostatic Water for Injection (BWFI) : This type of
water used for making parenteral solutions prepared
under aseptic conditions and not terminally sterilized.
Need to meet USP sterility test. It can contain an added
bacteriostatic agent when in containers of 30ml or less
• Sterile Water for Injection USP SWFI containing one or
more suitable bacteriostatic agents. Multiple-dose
containers not exceeding 30 ml. They are permitted to
contain higher levels of than WFI because of the possible
leaching of glass container. Sterile Water for Irrigation.
Wash wounds, surgical incisions, or body tissues.

14. Added substances (Additives)
• Antimicrobials: Added for fungistatic or bacteriostat
action or concentration Used to prevent the
multiplication of micro-organisms
• Ex.. Benzyl alcohol ------ 0.5 – 10 %
• Benzethonium chloride -- 0.01 %
• Methyl paraben ---- 0.01 – 0.18 %
• Propyl paraben --- 0.005 – 0.035 %
• Phenol --- 0.065 – 0.5 %
• Preservatives: Multidose containers must have
preservatives unless prohibited by monograph. Large
volume parenteral must not contain preservative becoz
it may be dangerous to human body if it contain in high
doses.

15. • Antioxidants : Used to protect product from
oxidation Acts as reducing agent or prevents oxidation
• Ex: A) Reducing agent: Ascorbic acid -- 0.02 – 0.1 %
Sodium bisulphite -- 0.1 – 0.15 %
Sodium metabisulphite -- 0.1 – 0.15 %
Thiourea - 0.005 %
B) Blocking agents : Ascorbic acid esters- 0.01– 0.015%
BHT- 0.005 – 0.02 %
C) Synergistic: Ascorbic acid , Citric acid , Tartaric acid
D) Chelating agent: EDTA- 0.01- 0.075 %

16. • Buffers:
• Acetates, citrates, phosphates are generally used.
Factors affecting selection of buffers: EXAMPLES :
Acetic acid , adipic acid, benzoic acid, citric acid,
lactic acid Used in the conc. of 0.1 to 5.0 %
• Physiologically compatible Ideally pH 7.4 (>pH 9 may
get tissue damage and < pH 3 pain and phlebitis).
• Chelating agents:
Examples: Disodium edetate – 0.00368 - .05 %
Disodium calcium edetate - 0.04 %
Tetrasodium edetate – 0.01 %

17. • Stabilizers: As parenterals are available in solution
form they are most prone to unstabilize Used to
stabilize the formulation Maintain stable
Examples:
• Creatinine – 0.5- 0.8 %
• Glycerin – 1.5 – 2.25 %
• Niacinamide – 1.25 -2.5 %
• Sodium saccharin – 0.03 %
• Sodium caprylate – 0.4 %

18. • Solubilizing agents:
Used to increase solubility of slightly soluble drugs they
acts by any one of the following:
solubilizers , Emulsifiers, wetting agents.
Examples: Dimethylacetamide , Ethyl alcohol Glycerin
Lecithin PEG – 40 castor oil PEG – 300 Polysorbate 20,
40, 80 Stabilizer additives Co-solvent Improve solubility
(~1000 X increase) Prevent potential for hydrolysis
Surfactant Suspension Improve solubility (~100 X
increase)

19. • Protectants :
Protect against loss of activity caused by some stress
that is introduced by mfging process or to prevent loss
of active ingredients by adsorption to process
equipment or primary packaging materials Liposomal
formulation and vaccines
Examples- Cryoprotectants and Lyoprotectants
Surfactants: Use in parenterals suspension and
emulsionfor melting powders and to provide
acceptable syringability . And solubilizing steroids and
fat soluble vitamins Examples- SLS

20. Tonicity- adjusting agents
 Used to reduce the pain of injection.
 Buffers may acts as tonicity contributor as well as
stabilizers for the pH.
 Isotonicity depends on permeability of a living
semipermaeable membrane
 Hypotonic : swelling of cells (enlargement) Hypertonic:
shrinking of cells (reduction)
 Example : Glycerin, Lactose, Mannitol, Dextrose
Sodium chloride and Sorbitol

21. • Methods for Adjusting Tonicity
Cryoscopic of Freezing Point Depression Method
Body fluid such as blood plasma and lachrymal secretion
fluid have freezing point of -0.52 0 c Hence all the solutions
which freeze at -0.52 0 c will be isotonic with these fluids.
%w/v of adjusting substance = 0.52-a /b
Where,
a- depression in freezing point due to the unadjusted solution or
sub.
b- depression in freezing point of 1%w/v of adjusting sub.

22. • E.g. Gate 2007
What Conc of NaCl require to make 1% soln of cocain HCl
isotonic with blood plasma.
Freezing point of 1 % w/vsolution of sod.cl- is 0.5760c &
Freezing point of 1 %w/v soln of cocain HCl is 0.090c
Ans: % of adjusting sub NaCl = 0.52-a/b
a= Freezing point of 1 %w/v soln of cocain HCl is 0.090c
b= Freezing point of 1 % w/vsolution of sod.cl- is 0.5760c
0.52-(0.09) = 0.746%
0.576

23. Sodium Chloride quivalent Method
E.g. Gate 2003
• What is the proportion of NaCl require to render a
1.5% solution of drug isotonic with blood plasma?
– Freezing point of 1 %w/v soln of drug is 0.122 0c and that
of NaCl is 0.5760c
Ans: Freezing point depression of 1 %w/v soln of drug is 0.122 0c
Freezing point depression of 1.5 %w/v soln of drug is= 0.122 x 1.5/1= 0.18330
Freezing point depression of blood= 0.52
So difference is 0.52-(0.1833)= 0.3367
1% = 0.576 , X= 0.3367 x1= 0.585
X% 0.3367 0.576

24. • White –Vincent Method:
• This method involves the addition of sufficient quantity
of water to a drug in order to prepare an isotonic
solution.
• V= w*E*111.1 Where,
• V – volume in milliliter of an isotonic solution that can
be prepare by dissolving w gm of drug in water
• E- NaCl equivalent of drug
• 111.1- Constant representing the volume in milliliter of
isotonic solution obtained by dissolving 1g of NaCl in
water
• Sprowls Methods:- Modified method of the white-
vincent which uses tables listing the volume V of
isotonic solution that can be prepared by mixing 0.3g
of a drug in water

25. Evaluation of parenteral preparations
• Particulate matter test
• Leakage test
• Clarity test
• Assay
• pH Identification test
• Turbidity Content uniformity
• Weight variation test
• Sterility test
• Bacterial endotoxin test (LAL test)
• Pyrogen test

26. • I. Sterility Testing
 Membrane filtration
 Direct inoculation of the culture medium
Sterility Testing: It is a procedure carried out to detect and conform absence
of any viable form of microbes in or on pharmacopeia preparation or product.
• II. Clarity Test
 Visual or automatic inspection for particulate matter
 Microscopic examination

27. OBJECTIVE OF STERILITY TESTING: For validation of
sterilization process. To check presence of microorganisms in
preparation which are sterile. To prevent issue of
contaminated product in market.
INDICATOR USED FOR STERILITY TESTING: INDICATORS are
characterized preparation of a specific microorganism that
provide a defined and stable resistance to specific sterilization
process.
CHEMICAL INDICATOR: e.g. Dichromate
BIOLOGICAL INDICATOR: TYPE 1: spores that are added in disc
, on filter paper, glass, plastic material etc.
TYPE 2: Spore suspension
TYPE 3: Self contain Indicator

28. Medium used in sterility testing
• Soyabean casein digest media: It is used to detect the
growth of aerobic bacteria, but when incubated at 25 o C it
will be suitable for the growth of fungi.
• Fluid thioglycolate: It is used to detect the growth of
anaerobic bacteria, It also could be used to detect the
growth of aerobic bacteria. It is anaerobic medium due to
presence of: Sodium thioglycolate and cystaine which act as
reducing agents. Small amount of agar to increase viscosity
of the medium thus decreasing convection current. Redox
indicator (MethyleneBlue) which change color of the
medium when 30% of the medium become oxidized.

29. • Fluid thioglycolate: It should be prepared in long tube O 2
anaerobic bacteria aerobic bacteria Alternative fluid
thioglycollate medium : same as FT medium but not
contain
• Sabaroud’s dextrose medium: It is suitable medium used to
detect the growth of fungi because: it has acidic pH.
contains dextrose which is readily fermentable sugar.
• IncubationTemperature: Incubate the media intended for
detection of bacteria at 35oC. Incubate the media intended
for detection of fungi at 25oC. Incubation Period: It should
be not less than 7 days. Control tests : Performed exactly
under the same condition as the test. Used to test the
media used in the sterility test.

30. Methods of Sterility test
Membrane Filtration: Suitable for samples with large volumes.
1. Filtering the sample through a membrane filter.
2. Aseptically cut the membrane into three equal pieces.
3. inoculate them on appropriate culture media.
Direct Inoculation: Suitable for samples with small volumes.
• Application of Sterility test to Different Dosage Forms
• 1) Aqueous Solutions: Tested directly by direct inoculation method if it is of
small volume or by membrane filtration method if it is of large volume.
• 2) Soluble Solids: Dissolve in a suitable solvent * Sterile. * Has no antimicrobial
activity. Such as: meat peptone or caseine peptone
• Oily Preparations: Add a suitable emulsifying agent * Sterile* Has no
antimicrobial activity. Such as: Polysorbate or Polyethoxyethanol. During
incubation, oily preparation should be shaken gently every day.

31. • 3)Ointments & creams: Dilute with a suitable diluent * Sterile * Has no
antimicrobial activity. Such as: isopropyl myristate. add a suitable
emulsifying agent.
•
• Procedure: Using the Direct inoculation method. Carry out the control
tests under the same condition of the experiment. Sterility Test for Water
for Injection
• Interpretation and Repeat Tests No contaminated units should be found.
A test may only be repeated when it can be demonstrated that the test
was invalid for causes unrelated to the product being examined.
• European Pharmacopoeia criteria (a) the data of the micro monitoring of
the sterility test facility show a fault (b) a review of the testing procedure
used during the test in question reveals a fault (c) microbial growth is
found in negative controls (d) after determination of the identity of the
microorganisms isolated from the test, the growth of this species or these
species may be ascribed unequivocally to faults with respect to the
material and/or technique used in conducting the sterility test procedure.

32. • III. Pyrogen Testing
• Pyrogens are bacterial products such as endotoxin
Can cause
• fever,
• activate coagulation system,
• alter carbohydrate lipid metabolism,
• produce shock and death
Main source of contamination of products is water

33. • i. LAL (limulus amoebocyte lysate) test for
endotoxin Utilises extract from blood cells of
horseshoe crab Contains an enzyme and protein
system that clots in the presence of endotoxin
• Extract from blood cells (Amoebocyte lysate) Enzyme + protein
Horseshoe crab (Limulus polyphemus) Endotoxins ~ 30 mins
Coagulation - Formation of gel Solution of test parenteral product
• ii. Rabbit test Based on temperature rise of rabbits
compared to controls following an injection of the
test product 1. Control Temperature 2. Injection of
test solution 3. Record of temperature after injection

34. • Particulate Matter Monitoring :
• Definition: Unwanted mobile insoluble matter other than gas
bubbles present in the given product. It may be dangerous when
the particle size is larger than R.B.C. & may block the blood vessel.
This type of products are immediately rejected from the batch.
• The limit test for particulate matter is prescribed in
I.P. 1996 (A- 125)
• Applicable for: 100 ml or more volume containers of
single dose LV given by IV infusion
• Not applicable for: Multidose injections Single dose SVP
Injectable solutions constituted from sterile solids
• Permitted limits of particulate matter Particle size in
micrometer Max.No.of particles (equal to or larger than)
per ml 10 50 25 5 50 Nil

35. • Sources of particulate matter Contamination
• Intrinsic contamination: Originally present in products e.g.
Barium ions may react or leach with Sulphur ion which are
already present in formulation may produce barium sulphate
crystals.
• Extrinsic contamination: Material comes from outside or
environment e.g. coming off the material from body & cloths
of person Entry of particle from ceiling , walls & furniture May
be in the form of cotton, glass rubber, plastics, tissues, insect
fragments, bacterial contamination, dust, papers etc…

36. • Methods of monitoring particulate matter
• Visual method: examined against strong illuminated screen
• Coulter counter method: particles less than 0.1 micrometer in
diameter.
• Filtration method: used for counting the particles in hydraulic
fluids
• Light blockage method: Used for hydraulic oils Allows stream
of fluid under test to pass between a bright white light source
& photoiodide sensor.

37. Significance of Particulate Matter monitoring
Its presence may causes:
• Septicemia Fever & blockage of blood vessels
• Quality of product may affect
As per USP
LVP :
• NMT 50 particles/ ml (size 10 or more than 10 micrometer)
• 5 particles/ ml (size more than 25 micrometer)
SVP:
• 10,000 particles/ container of size 10 micrometer or greater &
• NMT 1000 particles/ container greater than 25 micrometer.

38. • LEAKAGE TEST
 Performed in vaccume chember ,
 1% Methylene blue dye solution
 When vaccume is release, colour will enter in ampoule
with defective sealing presence of dye solution in
ampoule confirmed leakage & hence rejected
• CLARITY TEST
 against strong illuminated black and white screen, the
content of container are slowly inverted and rotated
 coulter counter,
 photo- nephlometer

39. 1) Primary packaging material
e.g. Bottle , Ampoules , Vials , Syringes , Cartridges ,
Bags
2) Secondary packaging material
e.g. Label & Cartons etc
MATERIAL OF CONSRTUCTION FOR PACKAGING
1) Glass 2) Plastic 3) Rubber 4) Paper

40. • COMPOSITION OF GLASS
Fused silica Allow contain 3 types of oxides
1) Oxides involving monovalent cation E.g. Na+
2) Oxides involving divalent cation E.g. Cao , Mgo
3) Oxides involving multivalent cation E.g. B2o3 , Al2o3
• TYPES OF GLASS
1 Highly resistance Borosilicate glass, Laboratory apparatus.
2 Treated soda lime glass, Container eye drops & other
dropper bottles.
3 Soda lime glass, Non aq.parentral products .
4 Non parenteral glass. (general purpose) Material other
than parental preparation.

41. EVALUATION TEST FOR CONTAINER
• Water attack test:
3 container filled 90% overflow capacity high purity water
autoclaving at 121 ◦c for 30 min 100 ml of combined extract
titrate with 0.02N H2SO4
 capacity 100 ml or less = 0.7 ml H2SO4
 capacity over 100 ml = 0.2 ml H2SO4
• Powdered glass test
Digest borosilicate flask 121◦c for 60 min Crash 6 container
sieving 40 / 50 10 gm powder + 50 ml high purity water
121◦c for 20 min Decent & titrate solution with 0.02N H2SO4
using indicator methyl red.

42. • Leakage test
Fill ten containers with water. Fit with the intended closures
and keep them inverted at room temperature for 24hours.
There are no signs of leakage from any container.

43. Sterile products Glass Ampoules
• Type I (borosilicate glass is used ) Packaging is 100% tamper proof .
• One point or colour break ring offers consistent breaking force . Up to
3 colour can be placed for identification purpose .
• Type of formulation: Ampoule Aqueous Injectables Of Any pH Type I
Aqueous Injectables Of pH Less Than 7 Type II
Non-Aqueous Injectables Type III
1) Tip sealing -
2) Pull seals -
Now a days, plastic ampoules for “water for injection” are available in the
market.
• Vial With Stopper : for multiple dose parenteral preparation
• Closure : Made from Butyl rubber ,Nitrile rubbers ,Neoprene , Silicon
rubbers.
• It has compression recovery, coring resistance, solvent resistance, heat
resistant , radiation resistance with very low water absorption and
permeability properties.

44. • TYPE & SHAPE OF RUBBER
• Natural – polyisoprene latex of free HEVEA BRAZILIENSIS
• Synthetic
a) Gray butyl
b) Nitrile rubber
c) Chloroprene
d) Silicon rubber
Shape of rubber closures
a) Flagged type
b) Slotted type
c) Plunger type

45. A) Merits
• Rubber is soft so that needle easily can be inserted & remove
• Production sterility is maintained after insertion & removal of
needle because of resistance
B) Demerits
• Sorption of active ingredient
• Loss of volatile compound
• Leaching effects

46. TYPE OF PLASTICS
A) Thermoplastic
a) polyethylene(PE): 1) LDPE (Low density polyethylene)
2) HDPE (High density polyethylene)
b) Ethylene vinyl acetate (EVA)
c) polypropylene
d) Cyclic olefin copolymer (COCS)
e) Polyvinyl chloride (PVC)
f) Polystyrene
B) Thermosets
a) Melamine
b) Phenol formaldehyde
c) Urea formaldehyde

47. Acidity & alkalinity test
• To a volume of solution corresponding to 4 per cent of the
nominal capacity of the container Add 0.1 ml of
phenolphthalein solution. The solution is colorless Add 0.4 ml
of 0.01M sodium hydroxide. The solution is pink. Add 0.8 ml
of 0.01M hydrochloric acid and 0.1 ml of methyl red solution.
The solution is orange-red or red.
Biological reaction test
• In Vitro test- extract placed in contact with mammalian cell to
check toxicity
• In Vivo test –
• Systemic injection test –mice
• Intracutanous test – rabbit
• Implantation test & eye irritation test- rabbit

48. REFERENCES
• Pharmaceutical Dosage Forms. Lieberman, Herbert A.
• Vol. 1: Parenteral Medications. Pharmaceutical Dosage Forms. Avis,
Kenneth E.
• Vol. 2: Parenteral Medications Pharmaceutical Dosage Forms. Avis,
Kenneth E
• Vol. 3 : Parenteral Medications Parenteral Quality Control. Michael
J. Akers and Daniel S. Larrimore (Marcel Dekker, second
edition.1993).
• Modern Pharmaceutics. Gilbert S. Banker, Christopher T. Rhodes.
Fourth Edition.
• www.google.com
• www.pharmaceuticalonline.com
•