Basic concepts of small and large volume parenteral solution

1. Manufacturing of Sterile
SOLUTION
Prepared By:
Dr. Kandekar Ujjwala Y.
JSPM’s Rajarshi Shahu College of Pharmacy and Research, Tathwade, Pune
Aseptic Process Technology

2. Solutions: Solution is a homogeneous one-phase system consisting of two
or more components.
Types:
A. Small Volume
B. Large Volume
A: Small Volume: An Injection that is packaged in containers labeled as
containing 100 ml or Less.
B: An Injection that is packaged in containers labeled as containing More.
Than 100 ml

3. During formulation following points should be consider :
1) Influence of route of administration- It places certain
requirements & limitations on the formulation the imp. one is volume.
I.V. is the only route by which volume more than 10ml can be
administered.
2) Selection of Vehicle :
Water is commonly used vehicle, when it is not possible to
use whole aqueous solution for physical or chemical reason,
addition of solubilizing agent or cosolvent (glycerin, ethanol,
propylene glycol) may be necessary.

4. TYPES OF VEHICLES:
• Aqueous
• Non-aqueous
AQUEOUS VEHICLES :
Water is used as vehicle for most injections because aqueous
preparations are tolerated by the body, safest and easiest for
administration.
TYPES:
-Water for injection
-Sterile water for injection
-Bacteriostatic water for injection
-Sterile water for irrigation

5. 1)WATER FOR INJECTION :
-It must be freshly prepared .
-It should be free from pyrogen and metabolic products of
microorganisms.
-Should not contain >10ppm of dissolved solid and
chloride ,sulfate, calcium, carbon dioxide.
For large installation close stainless steel containers are used and for
small installation sterile pyrogen free glass containers are used for
storage.
w.f.i. should be used within 24 hrs, it can be stored under specific
conditions extreme at 5 or 85⁰c. because due to excellent solvent
properties of water it is difficult to maintain the purity

6. WATER FOR INJECTION PREPARATION:
1. DISTILLATION
2. REVERSE OSMOSIS
Pretreatment of Water:
City water sand filter primary softener polisher
dechlorinator reverse osmosis storage tank
multiple effect still clean steam
generator
cool loop hot loop
• Chlorination suppress the microbial growth
• Pre-filter through depth filter remove iron or suspended matter.
• Water softening through ion exchange to remove alkaline earth
metals, calcium and magnesium thus reduce scale deposit.
• Deionization by ion exchange resins for removal of ions from feed
water.
• Activated carbon bed for removal of chlorine and organics and then
treatment with UV radiations.

7. 7
Soft Water Plant -
Sample Schematic
Water
Softener
#1
Water
Softener
#2
Water
Softener
#3
Multi
Media
#3
Multi
Media
#2
Multi
Media
#1
Soft
Water
Storage
Tank
Distribution
Pumps
Bisulfite
Addition
Hypochlorite
Addition
Hardness
Analyser
Utility Water
Inlet
User 1
User 2
User 3
User 4
User 5
User 6

8.  1)Distillation :
It is a continuous process of heating water to its boiling point so that
steam formed can be passed through separator and condensed into pure water
and discharged from apparatus.
 Metal stills are suitable for preparing w. f. i.
Factors to be considered while selection are-
a) Size of baffles :
should be large to provide sufficient space for vapor and to decrease
entrainment of distillate as a film or vapor bubbles.
b) Design of baffles :
Baffles determines the effectiveness of refluxing so should be properly
designed for efficient distillation.
c) Material of construction :
Parts of still that are in direct contact with water vapour should be
constructed of metal coated with pure tin or material should made up of 304 or
316 stainless steel or chemically resistance glass.

9. 2) Reverse osmosis : It is a process for separation of solutes from water by
applying pressure on a more concentrated solution in contact with a semi
permeable membrane to produce less concentrated solution.
Semipermeable membranes are of two types:
1) Spiral wound cellulose acetate
2) Hollow fiber polyamide

10. 10
Reverse Osmosis Water Generation -
Sample Schematic
RO
STORAGE
TANK
RO LOOP
RETURN
RO
DISTRIBUTION
SOFT WATER
BREAK TANK
ACTIVATED
CARBON FILTER
0.5 um
FILTER
RO
MEMBRANES
PUMP
RE-CIRCULATION TO TANK
SOFT
WATER
SOFT WATER
BREAK TANK
ACTIVATED
CARBON FILTER
0.5 um
FILTER
RO
MEMBRANES
PUMP
RE-CIRCULATION TO TANK
SOFT
WATER
RO Generation
Capacity 17 m3/ hr

11. Sterile water for injection :
Water is sterilized & suitably packed in a single dose container not more
than 100 ml capacity, dose not contain the bacteriostatic agent.
Higher total solid content is permitted in s. w.f.i than w. f.i. because of
possible leaching of glass constituents into water during sterilization and
storage.
This is appropriate type of water for making parenteral solution prepared
under aseptic condition and not sterilized by filtration or by autoclaving in
final container.
It is labeled to indicate that not suitable for I.V. use, without it first have
been made approx. isotonic by addition of suitable solute.

12. Bacteriostatic water for injection :
It should not be sold in containers larger than 30ml or NLT 5ml. Should
be injected at one time to prevent injection of larger amount of
bacteriostatic agent. (Phenol or Thiomarsal )
Sterile water for irrigation :
It is sterile and packed in single dose container. No antimicrobial agents
are added. Volume should not be more than 1 liter. Label should indicate, it
is for body cavity and wounds.

13. Other types of aqueous vehicles :
1) Water for injection free from Carbon dioxide :
Some drugs are formulated as the salt to enhance the solubility.
CO2 decomposes the salt & precipitate the free drug. Therefore to avoid
this CO2 can be removed by boiling w.f.i. for at least 10 min. Meanwhile
exposure to air should be minimized by covering the flask with small
inverted beaker.
2)Water for injection free from dissolved air :
Sensitive medicament can be protected from oxidation by using this
water.
Method of preparation is same as above.

14. NON – AQUEOUS VEHICLES :
1) Oils : Fixed oil or Ester or mixture of both.
It must not contain mineral oil or solid paraffin as these are not
metabolized by body. May cause tissue reaction or tumors. They must be
free from rancidity. Ex. Arachis oil, sesame oil, cotton seed oil.
Ester gives less viscous preparation which is not suitable for depot
therapy.
2) Alcohol : Not used widely, should be administered with care because it
has its own physiological activity and it causes tissue damage.
Benzyl & ethyl alcohol used in combination with other solvents in low
concentration & it is less harmless by I.M. route.

15. Propylene glycol :
It is non toxic. Causes severe irritation on S.C. or I.V. injection.
NON AQUEOUS VEHICLES ARE USED IN CASE OF :
Limited water solubility of medicament substance.
Susceptibility of drug to hydrolysis.
IDEAL PROPERTIES :
1) Non irritating, non toxic, non sensitizing.
2) Shouldn’t exit its own p’cological action.
3) Shouldn’t react with active medicament.
4) Viscosity must be as such to allow ease of application.
5) B.P. must be sufficiently high to permit heat sterilization.

16. ADDITIVES :
Criteria for selection :
•Non toxic
•colorants are never added
•shouldn’t interfere with therapeutic efficacy.
1) Solubilizing agents :
Used to maintain or increase the drug solubility.
Ex. Co solvents such as glycerin, ethyl alcohol, PEG, PG.
2) Buffers :
• Are added to many preparations to resist the change in pH due to –
degradation reaction within product.
•Interaction with container component ex. Glass, rubber.
• Absorption of evolution of gases.

17. •Ideal pH selection should be 7.4 extreme deviation from pH causes
complications such as tissue necrosis, extreme pain.
•For I.V. SVPs pH range is 3 to 10.5, for parenteral administered by other
routes pH range is 4 to 9.
Ex. Acetate, citrate, phosphate and glutamate.
3) Antioxidants :
Many drugs are subjected to oxidative degradation. Antioxidants can be
added in parenteral solution alone or in combination to avoid oxidation of
compound. Acts in 2 ways:
1)By being preferably oxidized and gradually consumed.
2)By blocking an oxidative chain reaction.
Ex. Salt of sulfur dioxide, bisulphite, metabisulphite.

18. 4)Chelating agent :
Are used to form complex with the drug involving more than one bond to avoid
degradation.
Ex. EDTA, citric acid, tartaric acid.
5) Antimicrobial agents:
Used to prevent the growth of microorganisms in preparation and to maintain
the product during its shelf life and use.
Types :
a) Quaternary ammonium compounds – mostly used in ophthalmic products.
ex. Benzalkonium chloride.
b) Alcohols :
ex. Benzyl alcohol, chlorobutanol.
c) Esters :
ex. Methyl p-hydroxy benzoate, propyl p-hydroxy benzoate, butyl p-hydroxy
benzoate.
d) Mercurials:
ex. Phenyl mercuric nitrates and acetates.

19. Criteria for selection of preservative :
•Non toxic in concentration used.
•Shouldn’t react with macromolecular drug.
•Should stable at given pH.
•No pharmacological action.
•Broad spectrum of activity.
•Low concentration.
Ex. Chlorobutanol, methyl paraben, benzyl alcohol.

20. 6) Tonicity adjusting agents :
These are used to minimize the tissue damage & irritation to reduce
hemolysis of blood cells & prevent electrolytic imbalance upon
administration of S.V.P. NaCl, KCl , and dextrose these electrolytes are
commonly added to adjust the hypotonic solution, non electrolytes such as
glycerin and lactose also can be added.

21. FORMULATION OF SMALL VOLUME PARENTERAL SOLUTION
Steps:
Step 1: Non-sterile Formulation
Water for Injection 120°C for 20min 60°C Cool
Step 2: Sterile Filtration.
Step 3: Aseptic Subdivision.

23. Formulation supporting studies:
1. Biological consideration:
a. Evaluation of impact of formulation towards hemolysis, precipitation,
phlebitis and pain on injection
b. Tonicity
Hemolysis: hypotonicity, effect of drug or formulation component on cell
membrane
Precipitation: solubilizing agents are removed
Phlebitis: inflamed vein, in severe cases leads to thrombus and severe
complications
Few causes of phlebitis –particulate matter, precipitation of the drug

24. Pain on injection: Pain may be associated with formulation ingredients.
e.g. macrolide antibiotics
Pain on injection may be immediate or delayed, can be reduced by adjusting
the tonicity, pH and adding anesthetic agents like benzyl alcohol.
b. Tonicity
2. Manufacturing and handling support studies:
a. Compatibility with diluents and IV sets: /
Many parenteral preparations are administered as LVP, potential for drug
stability and compatibility problem is great because of long duration of contact
time

25. 2. Manufacturing and handling support studies:
b. Compatibility studies with manufacturing equipment contact surfaces:
Various contact surfaces are encountered during manufacture and storage of
injection products. Compatibility studies of drug product with such surfaces must
be evaluated to ensure that there is no adverse interactions and quality of the
product is unaffected. Typically the component under investigation is placed in
contact with the drug product solution for 24 to 96 hrs. at room temperature,
samples are analyzed for various physicochemical attributes such as pH,
appearance, UV/FTIR spectroscopy and potency.
c. Compatibility with packaging components: During storage of the product in the
final container, the product comes in contact with the rubber based or polymeric
stoppers, glass or plastic bags. Compatibility studies with drug product with
packaging components is performed.

26. 2. Manufacturing and handling support studies:
d. Compatibility with membrane filters: Bulk solutions of many aseptically produced
injection products are sterilized by membrane filtration using 0.22 micron filter. Some
techniques used:
a. Microbial membrane retention testing to demonstrate that the formulation of the
product does not adversely affect the effectiveness of removal of any microbial
contamination from the bulk solution. This is done by filtering a challenge solution
containing large number of bacteria in the drug product solution and testing for the
filtrate for presence of microbes.
b. Membrane compatibility study to ensure that the prolonged exposure of the product
does not affect the key membrane characteristics. This is done by soaking
membrane disks in the drug bulk solution for 24 to 48 hrs. and then evaluating the
filter for key parameters such as flow rate, product bubble point, weight change, and
appearance.

27. 2. Manufacturing and handling support studies:
c. Filter extractability testing to assess the effect of formulation on the
extractable from the filter. This is done by subjecting filter device to worst
case sterilization condition such as time, temperature followed by extended
exposure to organic solvents such as 100% denatured ethanol and then
analyzing the extract for volatile and non-volatile organic compounds.

28. Feasibility of terminal sterilization: During Autoclaving drug may degrade or
interact with container. Material could leach from rubber closure, Antioxidant
and antimicrobial agents can be absorbed or consumed during sterilization.
Therefore product are prepared aseptically. Regulatory agencies may require
written justification to address why product is not terminally sterilized. With
such restrictions formulator must assess the effect of terminal sterilization,
acceptable level of degradant and alternative sterilization techniques.
Photostability: exposure to irradiation can influence stability leading to
photodecomposition of product. Which may lead to adverse reaction.
If amber color container is not enough to give protection against
photodegradation secondary packaging materials may be used

29. Formulation of Large Volume Parenteral:
Physiological parameters:
Some constituents in the human body a are affected by IV therapy. These are
water, electrolyte, carbohydrates, amino acids, lipids and micronutrients such
as vitamins, minerals and trace elements.
The living cell is bathed in tissue fluid kept in constant composition.
Alteration in composition or amount of tissue can cause significant
physiological derangement. Such imbalances may be due to illness, trauma or
surgical procedures. Under such circumstances it is necessary to anticipate and
correct deficits by administration of suitable fluids.
LVP formulation must be developed to ensure that desired level of solution are
administered in therapeutically active and available form. The formulator must
understand the biochemistry of the body and chemistry of the in vivo
parenteral.

30. Formulation Parameter:
Physiological:
Body fluid rapidly exchange water and electrolytes between the cells and
extracellular compartments, maintain equilibrium within and between the
compartments. The movement of solvent and solute through semipermeable
membrane is called osmosis. If a concentration of solute in adjoining
compartments differs, water moves rapidly into compartment with higher
concentration in the compartment with lower concentration.
The resistance to unrestricted movement between compartment is defined as
osmotic pressure and is expressed as miliosmoles per kilogram (mOsm/kg).
mOsmol/L= g/ L of solute/ mol. wt.of solute x 1000 x Number of ions.
Sodium Chloride has mol.wt. of 58.5 and forms two ions Na+ and Cl- in
solution. The osmolarity of 0.9 % solution calculated as
mOsm/L = 9/58.5 x1000x 2 = 307.7 (308) {RBC has osmolarity of 306}
If hypotonic and hypertonic solution used must be administered slowly.

31. Physicochemical Parameters:
Solubility: Most of the ingredients used in LVP are extremely soluble in
therapeutic concentration, once solubilized ingredient remain dissolved during
handling and storage. (exception is 15% solution of mannitol when cooled to
room temperature crystals starts precipitating out, solution is warmed prior to
use.
pH: the pH must be considered for following points:
Effect on body when solution is administered
Effect on stability of the product
Effect on container closure system
Possible degradation of the drug
The pH of the blood is 7.35-7.45 and effect of IV fluids outside this range
depends on buffer capacity of the solution, determined by amount of weak
acid or bases that are part of formulation. The solution is rapidly diluted in
blood stream and the body’s buffering system can maintain the proper pH
levels when high or low pH LVP’s are administered.

32. Vehicle: WFI is the vehicle used for all LVP’s. All ingredients are dissolved
and resulting solution is clear and colorless except IV fat emulsion.
Physical parameter’s:
The sensitivity of the light and extreme temperature must be evaluated.
e.g. vitamin formulation require protection from light.
Solution containing dextrose tends to develop discoloration when store
for prolog period or at high temperature.
Stabilization of LVP:
Added substances: buffering agents, chelating agents, antimicrobial
preservative and antioxidant are commonly added in parenteral are NOT
used in LVP’s as they can introduce large amount of fluid and chemicals into
the body.
Antioxidants such as sodium bisulphite or metabisulphite may be added.

34. VALUE ADDITION:
“Sixty years ago I knew everything; now I
know nothing; education is a progressive
discovery of our own ignorance.”
– Will Durant.