Parenteral products are sterile solutions, suspensions, or emulsions that are administered directly into the body by injection through various routes such as intravenous, intramuscular, or subcutaneous. They provide pure active ingredients free from contamination and immediate physiological effects. Parenteral formulations must consider factors like the drug's solubility, desired route of administration, dosage volume, and onset/duration of action. Common vehicles include water, isotonic saline solutions, and nonaqueous solvents. Additives like co-solvents and surfactants may also be included to aid formulation.

1. Parenteral Products

2. Introduction
• They are injected directly into the body tissue.
• They are exceptionally pure, and free from physical, chemical and
biological contamination.
• Some peptides, proteins and chemotherapeutic agents are only be
given parenterally because they are inactivated by the gastrointestinal
enzymes.
• Parenteral products are sterile and pyrogen free.
• May be solution, suspension or emulsion.
• May be large volume or small volume.
• Administered IV, IM, or subcutaneous and other limited routes.

3. Routes of administration - IV
• Injection into the vein.
• Rapid and predictable response.
• 100% bioavailability.
• Large volume administered as controlled rate infusion. generally solutions
or emulsions of the size of the disperse phase less than 1 micron.
• Due to the relative insensibility of veins walls, so, too irritant drugs can be
administered IV.
• Quick administration may lead to drug-induced shock.
• Training is essentially required.

4. • Into the muscle. Gluteal ( buttocks), vastus lateralis ( lateral thigh) or
deltoid ( upper arm) muscles.
• The volume is 1 – 3 ml or up to 10 ml in divided doses.
• Training is essential.
• Rapid absorption but less than iv
• Absorption is greater from aqueous solutions.
• Used for controlled-release formulation.
Routes of administration - IM

5. • Into the fatty layer located beneath the dermis.
• Slower onset, oily solutions and aqueous suspension exhibit slower
absorption than aqueous solution.
• Typically 1 ml.
• Viscous formulations are not generally administered SC.
• Sites for SC are legs, arms and abdomen.
• Is the route of choice for insulin.
Routes of administration - subcutaneous

6. • Intradermal: 0.1 ml for diagnosis as allergy and tuberculin test.
• Intra-arterial: used to administer radiopaque media to visualize
heart , kidney. And in anticancer drugs.
• Intrathecal : to administer drugs to the cerebrospinal fluid to
ensure that appropriate concentration of drug is obtained at site.
• Intradural and extradural: intradural involves injection within the
dural membrane of the spinal cord and extradural is outside the
dural membrane and within the spinal caudal canals. E.g spinal
anaesthesia.
• Intracardiac: direct into the heart muscle, in cardiac emergency.
Routes of administration - others

7. Advantages
1. An immediate physiologic response.
2. for drugs of poor bioavailability or degraded within the GIT.
3. For unconscious or uncooperative patients or patients with nausea
and vomiting.
4. There is control in the dose and frequency as it is usually done by
trained medical staff.
5. Local effects may be achieved e.g local anesthesia.
6. Serious electrolyte imbalance may be corrected by iv infusion.
7. Wide range of drug release profiles.
8. Total parenteral nutrition.

8. Disadvantages
1. More complicated manufacturing process due to requirement of
aseptic techniques, the level of training staff is high render hem
more expensive and costly.
2. Skills for administration for correct use.
3. Pain at the site of administration.
4. In allergic conditions, rapid and intense allergic reaction will result.
5. Difficult to reverse the effect unlike other routes.
6. Thrombophlebitis, extravasation, fluid overload and air embolism.
7. Difficulties in manufacturing.
8. Disposal of used devices.

9. Formulation
• Solutions; aqueous or oil-based.
• Suspensions; aqueous or oil-based.
• Emulsions.
Factors to be considered for formulation:
1. Solubility of the therapeutic agent.
2. Preferred route of administration.
3. Volume of dose.
4. Onset and duration of action.
5. Physiochemical properties of the therapeutic agent.

10. Solubility of the therapeutic agent.
• Freely soluble therapeutic agents in the chosen solvent either
aqueous or oil make it suitable for parenteral preparation.
• Moderately soluble , the use of co-solvent is the preferred strategy.
Or to be used as suspension but recrystallization of soluble drug
during storage.
• Low solubility in the chosen vehicle , parenteral suspension is the only
choice.

11. Preferred route of administration
• IV requires aqueous solutions and should not precipitate in the
blood stream. Emulsions of sufficiently small particle size.
• Suspensions may be administered either IM or SC. Aqueous
solution may be also administered IM or SC.

12. Volume of dose
• Large volume up to 500 ml administered IV.
• Small volume by all routes bearing in mind the restrictions of oil-
based suspensions.

13. Onset and duration of action
• IV have immediate effect, other route are slower.
• Absorption from aqueous solutions is more faster.
• Oil-based suspensions/ solutions and aqueous suspensions offer
prolonged pharmacological actions.
Examples:
- Soluble insulin (aqueous) , the onset 30 min, peak 2-3 hrs, duration 8 hrs.
- Intermediate/long acting insulin suspension; onset 1-2 hrs, peak 4-12 hrs
and duration 16-35 hrs.
- Triamcinolone acetonide aqueous suspension have duration of action 21
days.

14. Physiochemical properties of the therapeutic agent
• Properties affecting the rate of dissolution and hence absorption of
poorly soluble drugs:
1. Solid –state properties: crystalline form or polymorphic.
2. Solubility of insoluble salt forms: altering the salt alters the
solubility and hence the dissolution and absorption. Solubility of
protamine insulin is lower than soluble insulin, salt of zinc or
protamine and zinc has lower solubility and hence lower rate of
dissolution and so long duration of action.
3. Particle size: testosterone propionate particle size 40-100µm
duration of action 8 days, 50 - 200µmduration of action 12 days.
Testosterone isobutyrate 50-200µm duration 20 days.

15. • Noyes-Whitney equation:
δM/δt = DACs/h
δM/δt rate of dissolution, h the thickness of the unstirred diffusion layer
that surrounds each particle. D is the diffusion coefficient of the dissolved
drug molecule through the unstirred diffusion layer. A is the surface area
of the particle undergoing dissolution. Cs is the saturated solubility of the
drug ( the concentration of drug that exist in solution adjacent to the
dissolving particle.
• Stocks law:
δv/ δt = 2𝑟2(ps-pL )g / 9ἠL thus, reducing the rate of sedimentation of drug
particles will enhance the physical stability of suspension. increasing the
particle size will increase rate of sedimentation , decreasing the physical
stability, decrease the rate of dissolution leading to slower onset but
prolonged duration of action.

16. Vehicles
• Aqueous vehicles
• Aqueous isotonic vehicles
• Nonaqueous vehicles

17. Aqueous Vehicles - Waters
• Water for injection.
• Sterile water for injection.
• Bacteriostatic water for injection.
• Sterile water for irrigation. USP

18. Water for injection
• Appearance: clear, odourless, pH 5 – 7.
• Purified water underwent distillation or RO.
• Total dissolved solids not more than 1 mg in 100 ml.
• No added substances.
• Pyrogen free.
• May not be sterile.
• Most frequently used for parenteral formulations to be sterilized after
preparation.
• Must be stored in tight container at suitable temperature.
• Collected in sterile and pyrogen free container ( glass or glass lined)
• Must be used within 24 hours.

19. Sterile water for injection
• Water for injection been sterilized and packed in container of 1 L or less.
• Pyrogen free.
• No antimicrobial preservative being added.
• Intended to be used to reconstitute sterile solid and dilute sterile solution.
• May contain slightly more solid content.
• Must be added ascetically.

20. Bacteriostatic water for injection
• Sterile water for injection with suitable antimicrobial agent.
• Filled in vials of volume not more than 30 ml.
• Name and concentration of preservative must be stated.e.g 0.9%
benzyl alcohol.
• Intended for small volume injectables.( multidose vials)
• Not to be used with large volume parentrals usually with 5 ml or less .

21. Sterile water for irrigation
• Available as sterilized and packaged in a single dose container.
• No added substances.
• Packaged in a container 1L or larger,
• Not intended for parenteral use.
• Labelled as “ For Irrigation Only”.

22. Pyrogens
• Fever producing compounds.
• Primarily associated with Gram-negative bacteria.
• Thermostable, thereby invalidating their removal by simple heating cycles.
• Water-soluble , thereby invalidating their removal using conventional
filtration techniques.
• Unaffected by bactericides.
• Removed by distillation or RO.
• Removal from storage container performed by heating at 250˚C for 30-45
minutes. Or at 180 ˚C for 3 -4 hours.
• Following water for injection must be stored in pyrogen-free container at
either 5 ˚C or 60 -90 ˚C if the period extended more than 24 hours.

23. Aqueous isotonic vehicles
• Sodium chloride injection: sterile isotonic solution of sodium
chloride in water for injection. No antimicrobial agent, used as a
vehicle solutions or suspensions for parenteral use.
• Bacteriostatic sodium chloride injection: sterile isotonic solution
of sodium chloride containing one or more specified antimicrobial
agent of a volume not more than 30 ml.
• Ringers injection: sterile solution of sodium chloride, potassium
chloride and calcium chloride in water for injection in a
physiological concentrations and can be used as vehicle or
electrolyte replenisher.
• Lactated Ringers injection: ringers solution + sodium lactate. Used
for electrolyte replenisher and systemic alkalizer.

24. Nonaqueous vehicles
• Must be nontoxic, nonirritant, nonsensitizing and not exert adverse
effect on ingredients of the formulation.
• Physical properties should be evaluated ( density, viscosity, miscibility,
polarity, stability, solvent activity and toxicity)
• Solvents that are miscible with water: Dioxalanes, butylenes glycol,
polyethylene glycol 400 and 600, Diimethylacetamide, propylene
glycol, glycerin and ethyl alcohol.
• Water-immiscible solvents: fixed oils ( corn oil, cottonseed oil, peanut
oil and sesame oil. Ethyloleate, isopropyl myristate and benzyl
benzoate.

25. Additives – Excipients
 Co-solvents
 Surface-active agents and/or suspending agents.
 Buffers
 Tonicity contributors.
 Preservative.
 Antioxidants.
 Stabilizers.

26. Co-solvents
 Glycerol
 Ethanol ( high concentration cause pain)
 Propylene glycol.
 Polyethylene glycol
 Polyethylene glycol 400
o for veterinary 2-pyrrolidone and dimethylacetamide may be used.
• The concentration of the co-solvent used should be sufficient to
render the drug soluble within the formulation.

27. Surface-active agents and/or suspending agents.
• Employed to enhance the solubility of the therapeutic agent in
concentration exceeding its critical micelle concentration.
• To enhance the physical stability of the formulation by adsorbing to the
surface of the dispersed therapeutic agent and preventing caking in
concentration below its critical micelle concentration. ( non-ionic
surfactants)
- Tweens series 0.1 – 0.5 % w/v
- Poloxamers 0.01 – 5% w/v.
- Lecithin 0.5 – 2% w/v.
• Surfactants with low hydrophile-lipophile balance are employed for oil
based vehicles and higher for aqueous based vehicles.
• Steroids are solubilized by Tweens and Span series.
• Amphottericin B is commericially available as a complex with sodium
deoxycholate ( Fungizone).

28. Buffers
• To maintain the solubility of the therapeutic agent over the
shelf life. Precipitated formulation should no longer be used
as it may cause capillary blockage.
• Acceptable pH 4- 9. below 3 will cause extreme pain and
above 9 will cause tissue necrosis.
• Citrate buffer, acetate buffer, phosphate buffer and glutamate
buffers ate commonly used.

29. Tonicity contributors
• Isotonic solution is that exhibits the same effective osmotic pressure
as blood serum.
• Ideally the administration of parenteral IV should be isotonic ( 291
mosmol/L).
• NaCl, dextrose are used to correct the isotonicity and the mass
required can be calculated by the gram-molecular concentration or
freezing-point depression of the solution.

30. Gram-molecular concentration
• Number of moles in 100 gms of solvent.
• A solution is isotonic whenever the gram molecular concentration is 0.03%.
• Dextrose is non-ionic , 1 mol when added to 100 gms of water will produce a
gram molecular concentration 1%, therefore to produce isotonic solution
0.03 × 180 ( molecular weight of dextrose) = 5.4% w/v.
• NaCl is ionic, 1 mol when added to 100 gms of water will produce a gram-
molecular concentration 2%, therefore to produce isotonic solution 0.03 ×
58.5/2 = 0.9% w/v.
• Lidocaine Hcl 1% solution, molecular weight 270 gm/mol, each mol dissociate
to produce 2 mols of ions hence, 2 ×1/270 = 0.007%. The difference from
isotonic is 0.03 – 0.007 = 0.023% , thus the amount od Nacl required to
render it isotonic is 0.023 × 58.5/2 = 0.67% w/v.

31. Freezing-point depression
• An isotonic solution exhibits a freezing point depression of 0.52 C.
• Inclusion of ions will lower the freezing point of a solution.
• The freezing point depression of 1% Nacl is 0.576 C ( from tables),
therefore the concentration of Nacl required to render the solution
isotonic is ( 0.52/0.576) ×1= 0.9%.
• The freezing-point depression of lidocaine Hcl 1% is 0.130 C. the
difference is 0.52 – 0.13 = 0.39 C. To render this isotonic by 1% Nacl ,
( 0.39/0.576) = 0.677 gm.

32. Preservative
• For multidose preparations.
• When there is no terminal sterilization.
• Methyl and Propyl parabens 9:1 are often used in concentration of 0.2% w/v.
• Phenol 0.25-05% or chlorocresol 0.1-0.3% w/v.
• Increasing the concentration up to 0.25%w/v
• Preservative should not interact with the container or the therapeutic agent
and should not be toxic.
• Oil-based product don’t require preservative.

33. Antioxidants
• To protect therapeutic agent from oxidation particularly under the
accelerated conditions of thermal sterilization.
- Reducing agent: ascorbic acid, sod metabisulphite, sod bisulphate, thiourea.
- Blocking agent: ascorbic acid, tocopherol.
- Synergistic agents: ascorbic acid, citric acid,tartaric acid , phosphoric acid.
- Chelating agent: EDTA.
- Protect from formation of free radicals: butylated hydroxyanisole, butylated
hydroxytoluene.
- Flushing the container with nitrogen.

34. Stabilizers
• Hydrophilic polymer to increase the viscosity of aqueous suspension.
• Lipophilic polymer for oil-based suspension as aluminium salts of
stearic acid, trihydroxystearin ( Thixcin).
• Stabilizers as Glycine, creatinine are added to ensure the stability of
drug compound in the preparation.

35. Manufacturing of parenteral formulations
Methods of sterilization:
1. Moist-heat sterilization.
2. Dry-heat sterilization.
3. Filtration sterilization.
4. Exposure to ionizing radiation.
5. Gas sterilization.

36. Moist-heat sterilization
• Performed on an autoclave and employs stream under pressure.
• Mode of action due to denaturation/coagulation of microbial protein.
• Increase in the pressure enables the temperature to increase.
• Pressure of 103.4 Kpa ( 15 pound/inch) and temperature 121˚C,
sterilization will be achieved in 20 minutes.
• Used for materials that are thermostable: glassware, dressings,
closures, aqueous solutions

37. Dry-heat sterilization
• Organism is destroyed by cellular dehydration followed byprylosis
/oxidation.
• Performed in ovens.
• 170 ˚C for 1 hour
• 160 ˚C for 2 hours
• 140 ˚C for 4 hours.
• Thermostable materials that can not be sterilized by moist heat.
• Oils, glycerin, propylene glycol, glass ware, thermostable therapeutic
agents and excipients.

38. Filtration
• 0.22 µm pore diameter.
• To maximize filter lifetime use series of filters 1, 0.45 then 0.22.
• For materials that are thermolabile.
• The container should be sterile.

39. Ionizing radiation
• Gamma radiation 25 – 40 kGy
• Expensive for routine, requires specialist.
• Used for terminal sterilization for materials being manufactured
under aseptic condition and not sterilized.
• Can cause some stability problems to some agents.

40. Gas Sterilization
• ETO, and propylene oxide.
• Moisture 60% and temperature 55 ˚C
• Mainly used to sterilize medical devices.
• Due to toxicity , ventilation measures after sterilization is required.

41. Production facilities- Functional areas
• Warehousing
• Compounding
• Materials
• Preparation
• Filtration and sterile receiving.
• Aseptic filling
• Stoppering
• Packaging
• Labeling
• Quarantine
Aseptic areas barriers:
- Sealed walls.
- Manual or automatic doors.
- Airlock pass through.
- Plastic curtains.

42. Flow plan
• Flow from the warehouse to compounding area for the ingredients.
• From warehouse to support area for other materials and containers.
• After processing , flow to the controlled aseptic area.
• Filling then quarantine
• OR filling, sterilized then quarantine

43. Clean room classification
European grade US classification ISO Not larger than 0.5
µm/ cubic feet
5 µm or larger
1 3 1
10 4 10
A - B 100 5 100
1000 6 1000 7
C 10,000 7 10,000 70
D 100,000 8 100,000 700
For class 10,000 , air velocity 100ft/ min. number of air changes 60 /hour.
This can be achieved by the use of HEPA filters. And HVAC system and pressure control.

44. Laminar-flow

45. Maintenance of clean rooms
personnel

46. Production procedures
1. Cleaning the container: WFI and air.
2. Automatic washing machine.
3. Sterilized then discharged to the filling room.
4. Closures , agitation in hot mild water detergent and rinsed with
WFI. Wet closures are then sterilized and stored ready to use. (
basket type automatic washing machine).
5. Equipment disassembled, brushed cleaned and steamed. SIP
6. Preparation of the product is the same as those used for
nonsterile.

47. • Filtration Membrane filter of 0.2 µm pore size. Cellulose esters, nylon,
polysulfone, polytetrafluoroethylene 9 Teflon).
• Filling : aseptic fill after filtration. Filling under blanket of HEPA filter
laminar- flow
- Volumetric filling involves the use of pistons
- Time-pressure or gravity filling during fixed time.no pumping.
- Net weight filling. This involves the use of the container.
Solids filling: flowability, filling by weight control. Vacuum may be
employed

48. Solid filling

49. Sealing of ampoules & vials
• Bead-sealing
• Pull sealing.
• Melting glass in a high
temperature oxygen
flame.
 Vials are closed
automatically by
rubber and held in
place by aluminulm
cap.

50. Terminal sterilization
• Moist-heat
• Dry heat
• Ionizing radiation
according to liability of the active ingredients.

51. Lyophilization

67. Containers & Closures
• Glass or plastic.
• Ampoules
• Vials
• Syringes
• Cartridges
• Bottles
• Bags
- Rubber stoppers and plungers
- Aluminum screw caps.

68. Glass containers
• Composed from silicon dioxide + other oxides ( sod, pot, calcium,
iron, mag, aluminum, boron.
• Other oxides rather than boric oxide are loosely bound to the silicon
oxide network thus they may be leached into a solution during
increased temperatures.
• They may hydrolyze and raise the pH.
• Types of glass:
- Type I, borosilicate glass 81% + 13%, less leachable oxides, chemically
resistant, low thermal Coefficient of expansion CoE.
- Type II, a soda lime treated glass.
- Type III, a soda lime glass.
- Type IV, Nonparenteral soda soda lime glass.

69. • Type II and Type III contain sodium oxide up to 14% and calcium oxide
up to 8%. They are chemically less resistant, higher CoE. Melt at lower
temperature making it easy to mold.
• Type II has les migratory oxides than type III.
• Type II has been treated under controlled temperature and humidity
with sulphar oxide or other dealkalizer to neutralize the interior
surface of the container to increase the chemical resistance. Although
repeated exposure to heat and alkaline detergents break this surface.
• Water attack test and the powdered glass test to determine the intact
surface of the container and to determine the leaching potential
respectively.
• Glass can be a source of leachables/extractable, particulates, can
cause adsorption of the ingredients and cracks.

70. Plastic containers
• Three problems related to plastic containers:
1. Permeation of vapour and other molecules through the walls.
2. Leaching of constituents from plastic into the product.
3. Sorption of drug molecules on the plastic material.( insulin, vit A
and warfarin)
• Polyethylene, polypropylene, PVC.

71. Rubber closure
• Elastomer , natural rubber latex treated with sulfar and peroxides as
curing agents, zinc oxide, stearic acid as activaters, antioxidants,
plasticizers, lubricants, fillers as carbon black, clay and barium
sulphate, pigments.
• Factors to be considered are elasticity, hardness, permeability,
tendency to fragment.
• Slippery. Silicon oil is traditionally used.

72. Needles
• SS made.
• Hollow canal with sharp head.
• Needle size is refered as gauge G. ( 11 – 32G)
• Winged needles for heparin.
• Plastic needles are available.
• G 15 – 25 for IV, 19 -22 G for IM, 24 – 25 G for SC, 25 – 27 G for children.

73. Quality Control Tests for Parenteral Products
1. Sterility tests
2. Clarity test
3. Leaker test
4. Pyrogen test

74. Sterility test – Direct Transfer Method
• Inoculation of required volume of sample in sterile fluid of
thioglycolate medium and other tube of soyabean-casein digest
medium.
• Incubation period is 14 days.
• Temperature for thioglycolate medium is 30 -35 ˚C to test for
anaerobic bacteria and for soyabean-casein digest medium is 20 – 25
˚C to test for aerobic bacteria and fungi.

75. Sterility test – Membrane Filtration Method
• Filtration of required volume of sample through sterile membrane silter of 0.22 (
0.45) pore size and diameter 47 mm under vacuum. Then slit the flter membrane
into two parts and inculate one part into fluid of thioglycolate medium and the
other part into tube of soyabean-casein digest medium.
• Incubation period is 7 days for terminal sterilization and 14 days for aseptic filling
process.
• Temperature for thioglycolate medium is 30 -35 ˚C to test for bacteria and for
soyabean-casein digest medium is 20 – 25 ˚C to test for fungi and yeast..

76. Clarity Test
• To test for particulate materials.
i. Clarity test apparatus, visual check against black and white
background.
ii. Filter paper method. Filter and examine microscopically.
iii. Automatic image analysis device using screen.
iv. Light absorption, light scattering and change in the electrical
resistance.

77. Leaker test
• Dipping the ampoule deeply in a coloured dye solution 1% methylene
blue is used.
• The process is carried out in a vacuum chamber under negative
pressure.
• When the vacuum is released the colour solution will enter the
ampoule of defective sealing.
• Not carried for vials and bottles.

78. Pyrogen Test – Rabbit test
• The test sample is to be injected into the ear vein of 3 rabbits. Body
temperature of the animals will be examined by rectal thermocouple and
the temperature is measured by electronic thermometer after 3 hours.
• If no any increase in temperature the product is considered pyrogen-free.
• If any rabbit shows rise in temperature by 0.6˚C or more, the test will be
repeated on 5 additional rabbits.
• If not more than 3 out of 8 rabbits show individual rise in temperature of
0.6˚C and sum of maximimum rise in temperature of all rabits is not mre
than 3.7 ˚C, the test is considered as complying the requirements.

79. Pyrogen test – Limulus amebocyte lysate test
LAL
• The amebocyte of horseshoe crab contains enzyme or protein system
that coagulates in the presence of small amount of
lipopolysaccharide.
• 0.1 ml of the test sample with cell lysate from amebocyte of
horseshoe crab incubated for 1 hour at 37 ˚C .
• The mixture is analyzed for the presence of gel clot.
• Bacterial endotoxins cause formation of gel.
• No gel = no coagulation = no any endotoxin present.
• It is the most liable test.