Large And Small Volume Parental – Physiological And Formulation

Consideration, Manufacturing And Evaluation.

INTRODUCTION

 The term of parenteral is derived from Greek word para meaning outside and enteron
meaning the intestine.

 Thus parenteral administration should include the administration of drug by any route other
than oral route.

 Parenteral drugs are administered directly in to the veins, muscles or under the skin , or more
specialized tissues such as spinal cord.

 Parenteral are sterile solutions or suspension of drug in aqueous or oily vehicle.

 Parenteral products are considered to be those sterile drugs, solutions, emulsions, suspensions.

 Term parenteral used for any drug/fluid whose delivery doesn’t utilize the alimentary canal for
General Requirements

 Stability

 Sterility

 Free from pyrogens & toxins

 Free from foreign particles

 Isotonic

 Chemical purity

 pH
PARENTERAL ROUTES

 The term parenteral literally means to avoid the gut (gastrointestinal

tract) and refers to any route of administration outside of or beside
the alimentary tract.

 Thus, parenteral are injectable drugs that enter the body directly and
are not required to be absorbed in the gastrointestinal tract before
they show their effect.

 Parenteral routes of administration usually have a more rapid onset

of action than other routes of administration.
ADVANTAGES

1. An immediate physiological response can be achieved if necessary, which can be of prime

consideration in clinical condition such as cardiac arrest, asthma and shock .

2. Parenteral therapy is required for drugs that are not effective orally or that are destroyed by
digestive secretions such as insulin other hormones and antibiotics.

3. Drug for uncooperative, nauseous or unconscious patients must be administered by

injection.

4. When desirable, parenteral therapy gives the physician control of the drug since the patient
must return for continued treatment, also in some cases the patient cannot be relied upon to
take oral administration.

5. Parenteral administration can results in local effect for drugs when desired as in dentistry
and anaesthesiology.
6. Rapid onset of action

7. Providing sustained drug delivery (implants, im depot inj)

8. Avoid first pass metabolism

9. Can inject drug directly in to a tissue (target drug delivery)

10. Useful for delivering fluids, electrolytes, or nutrients (TPN)

11. Can be done in hospitals, ambulatory infusion centers and home health care centers

12. Complete bioavailability.

DISADVANTAGES

 Pain on injection

 Difficult to reverse an administered drug’s effect.

 Sensitivity or allergic reaction at the site of injection.

 Requires strict control of sterility & non pyrogenicity than other formulation.

 Trained person is required.

 Require specialized equipment, devices, and techniques to prepare and administer drugs.

 More expensive and costly to produce.

ROUTES OF ADMINISTRATION
1. Subcutaneous:The injection of the drug under the
skin into the fatty layer, but not into the muscle.
Absorption of the drug is rapid. Eg; insulin
2. Intramuscular:Drugs are injected deeply into
muscle tissue. If the drug is in aqueous (water)
solution, absorption is rapid. However, if the drug is
in an oily liquid or in the form of a suspension, it can
prolong the release of the drug.
3. Intravenous : The injection of a drug directly into
the patient's veins, resulting in the most rapid onset
of action.
4. Intra dermal:The drug is injected into the top few
layers of the skin. Ideally, the drug is placed within
the dermis. Used for diagnostic agents.
 TYPES OF PARENTERALS

1. Small volume parenterals (SVP)

2. Large volume parenterals (LVP)

 SMALL VOLUME PARENTERALS

Definition:

According to USP “ an injection that is packaged in containers labeled as containing 100 ml or less

All the sterile products packaged in vials, ampoules, cartridges, syringes, bottles or any other container that is
100 ml or less fall under the class of SVP.

Ophthalmic products packaged in squeezable plastic containers, although topically applied to the eye rather than
administered by injection, also fall under the classification of Small Volume Injections (SVI) as long as the
container size is 100 ml or less.

SVP aqueous solutions can be administered by intravenous route because of local irritation.

Small volume parenteral products can be formulated and packaged in several ways and include a wide variety of
products like : Pharmaceutical products, Biological products, Allergenic extracts, Radiopharmaceutical products,
Genetically engineered or biotechnology products, Liposome and lipid products.
An injection is a preparation intended for parenteral administration and/or for constituting or diluting a
parenteral article prior to administration.

Classification of SVP:-
1. Single dose ampoules (glass/plastic )
2. Multiple dose vials
3. Prefilled syringes

Definition:- According to the USP 24/ NF 19 “As those preparations intended for injection through the skin or
other external boundary tissue, rather than through the alimentary canal”

So that the active substance they contain are administered using gravity or force directly into a blood
vessel,organ,tissue or lesion.
1. Ampoules

Sealed glass containers with an elongated neck that must be broken off.

Most ampoules are weakened around the neck for easy breaking; these will have
a colored band around the neck.

A 5 micron filter needle should be used when drawing the contents of an ampoule into a syringe since glass
particles may have fallen inside the ampoule when the top was snapped off.

 In addition, it is useful to wrap an alcohol wipe or small piece of gauze around the top of the ampoule before
breaking it.

This will provide some protection to the fingers if the ampoule shatters and will also reduce the possibility of
glass splinters becoming airborne.
2. Vials

Drugs and other additives are packaged in vials either as liquids or lyophilized powders.

Made of glass or plastic and are sealed with a rubber stopper.

 A needle is used to add contents to or withdraw contents from the vial.

Before withdrawing contents from a vial, an equal volume of air is usually injected into the
vial to pressurize the vial and aid in withdrawing the contents.

Vials may be designated for single-dose or multi-dose use.

Multi-dose vials contain a preservative to inhibit bacterial contamination once the vial has
been used
3. Dry powder

Dry powder formulations are lyophilized or freeze-dried powders that must be reconstituted with some suitable
solvent to make a liquid formulation before being withdrawn from the vial.

Some drugs are not stable in liquid form and so these drugs are put into the powder form and reconstituted just
prior to use.
There are several solvents that might be used to reconstitute the dry powders; The most common solvents are
Sterile Water for Injection, Bacteriostatic Water for Injection, Sodium Chloride Injection etc.
4. Prefilled Syringe

It consists of syringes which are prefilled with the drug solution.

There are two varieties of prefilled syringes. One type, a cartridge type package, is a single syringe and needle
unit which is to be placed in a special holder before use.

 Once the syringe and needle unit is used, they are discarded but the holder is used again with a new unit.

 The other type of prefilled syringe consists of a glass tube closed at both ends with rubber stoppers. The prefilled
tube is placed into a specially designed syringe that has a needle attached to it.

 After using this type or prefilled syringe, all of the pieces are discarded
 LARGE VOLUME PARENTERALS

 The USP provides the definition for large volume parenterals (LVP’s) which applies to an injection that is
intended for intravenous use and is packaged in containers holding 100 ml or more.

 LVP’s means a sterilized aqueous drug products packaged in a single dose container with a capacity of 100 ml or
more.

 It includes IV infusions, irrigating solutions, peritoneal dialysates and blood collecting units with anticoagulant .

A single-dose IV fluids packaged in bags or bottles containing more than 100 mL. (up to 1-2 liters).

Infused continuously / intermittently over 24 hours.

No anti-microbial agents added in LVP.

Isotonic, Sterile, Pyrogen-Free, free of particulate matter.

Large-volume parenteral (LVP) preparations—or, simply, LVPs—are sterile solutions of 250 mL or greater that
are administered parenterally.
The most common LVPs are IV solutions compounded from a standard solution or base solution such as 0.9%
sodium chloride (also known as NS), dextrose 5% in water (D5W), dextrose 5% in normal saline (D5NS), and
LR (Ringer's lactate) solution

The most common volumes for LVPs are 250 mL, 500 mL, and 1000 mL

These IV solutions can be administered as either a continuous infusion or a drip

1. Continuous Infusion :

 A continuous infusion—also called a maintenance infusion, replacement infusion, or hydration infusion—

typically consists of a base solution with additives

 A continuous infusion is used to:

 prevent or correct dehydration and restore electrolyte balance in a patient whose condition impedes adequate
fluid consumption

 replace fluids in a patient who has experienced significant blood loss from trauma or a surgical procedure

 provide easy vein access for blood draws and medication administration in a patient during a hospital stay
2. Drip

 A second type of LVP solution is referred to as a drip

 unlike continuous infusions, drip solutions are used to continuously deliver an IV medication to treat a specific
medical condition

 A physician may order an IV drip to be “titrated to effect”

 in this instance, a medication such as nitroglycerin is administered at such a rate as to relieve the patient’s chest
pain
 LVP-IV Fluids-Rationale of Uses
60-70% of human body weight is comprised of fluid (Water containing electrolytes, nonelectrolytes (glucose),
minerals, vitamins, blood cells etc).

The body is able to replace, at best, only about one-third of what it loses during exercise (fluids, calories &
electrolytes).

However, severe body fluid deficit / loss due to dehydration, vomiting, diarrhea, trauma, burn etc results in
improper functioning of nervous, cardiac, muscular, respiratory and digestive systems (death in severe loss of body
fluids)

Glucose / Fats / protein provide energy required to the cells.

Electrolytes and minerals are necessary for fluid balance, acid-base balance, muscle contractions and
transmission of nerve impulses.

Administration of IV fluids containing these essential substances are very important to recover the lost body
fluid (water, energy, electrolytes etc) to save the life of the patients.
 Physiology of Fluid Balance
Water is a critical element of the human body, composing approximately 70% of the body’s weight

primarily found within the cells of the body, or intracellular spaces, but it also can be found in the spaces between
the cells, or interstitial spaces, and in the spaces outside the cells, or extracellular spaces

also a component of blood vessels, where it is found in the intravascular spaces

Maintaining the proper level of fluid and electrolytes within the body, called homeostasis, is essential for human
life

fluid enters the body through the normal processes of drinking and eating and exits the body through the processes
of perspiration, respiration, urination, and bowel evacuation

When certain conditions affect normal fluid intake and output patients may be at risk for dehydration

occurs when the amount of water entering the body is less than the amount of water leaving the body

extreme loss of fluid may lead to kidney failure, cardiac arrest, or death

the quickest method of rehydration is through the injection of parenteral solutions into the blood supply
 Properties of Parenteral Products

Because parenteral products are administered directly into a patient’s blood supply, these solutions must have
certain chemical properties or characteristics that render them safe for patient administration

some characteristics include pH value, osmolarity, osmolality, and tonicity, as well as the compatibility of CSP
additives
1. pH Value

 The degree of alkalinity or acidity of a solution is referred to as its pH value and is measured on a scale from 0 to
14

 any solution with a pH of less than 7.0 is considered to be acidic

 any solution with a pH greater than 7.0 is considered to be alkaline

 a solution with a pH of 7.0 is considered to be neutral

 Human blood plasma has a pH of 7.4, which is slightly alkaline

 the pH of blood plasma must be maintained for optimal health

 Some facilities inject a buffer solution, such as sterile sodium bicarbonate, into the CSP to neutralize the pH and
prevent patient discomfort.
2. Osmolarity and Osmolality

 Osmolarity is a measure of the number of milliosmoles of solute per liter of solution (mOsm/L)

 osmolarity refers to the osmotic pressure applied by a solution across a cell wall

 osmotic pressure is the pressure required to maintain equilibrium within the cells

 Osmolality is a measure of the number of milliosmoles of solute per kilogram of solvent

 osmolality refers to the number of ions or molecules in a solution

 Osmolarity and osmolality affect the flow of fluid into and out of cells within the body

 To maintain optimal health, the cells should be maintained in a state of equilibrium

 CSPs must be neither hyperosmotic nor hypoosmotic

 this state of equilibrium is called isoosmotic, meaning that the solution has relatively the same number of
dissolved particles and the same osmotic pressure as human blood plasma
3. Tonicity
 Tonicity refers to the way that cells or tissues
respond to surrounding fluid
 A hypertonic solution contains a greater number of
dissolved particles than human blood plasma
 A hypotonic solution contains fewer dissolved
particles than human blood plasma
 An isotonic solution contains a number of
dissolved particles equivalent to human blood
plasma
Some conditions require treatment with a parenteral solution that is either hypertonic or hypotonic

Total parenteral nutrition (TPN) and other hypertonic solutions are generally administered into larger veins such as
the subclavian vein or the superior vena cava

these larger veins have significantly more blood flowing through them and can more easily accommodate the
hypertonic solution

Unlike hypertonic solutions, hypotonic solutions, are rarely administered to patients

occasionally, critical care patients who are experiencing diuresis are treated with these solutions to replace the high
volume of fluid output without significantly increasing plasma sodium concentration (PNa)

these patients must be monitored closely to ensure that they do not develop a potentially life-threatening electrolyte
imbalance such as hyponatremia
4. Compatibility

 Compatibility may be defined as the ability to combine two or more base components or additives within a
solution, without creating a resultant change in the physical or chemical properties of any of the solution
components or additives

 a CSP comprised of one or more incompatible components may result in a change to the physical or chemical
characteristics

 this undesirable change is called an incompatibility and may be dangerous to the patient recipient
 Formulation of Parenteral Products
 Depending on the nature of drug with respect to its physical and chemical characteristics and therapeutic
consideration the parenteral form is decided.
 If it is unstable in solution, drug may be prepared as dry powder intended for reconstitution with proper solvent at
time of administration or prepared as solution.
 If drug is unstable in water, then solvent may be replaced in part or totally by a solvent in which drug is insoluble.
 If drug is insoluble in water, an injection may be prepared as an aqueous suspension or as a solution in suitable
non aqueous solvent like vegetable oil.
 If an aqueous solution is desired, water soluble salt form of the insoluble drug is frequently prepared.
 Aqueous or blood miscible solutions may be injected directly into blood stream.
 Blood immiscible liquids, such as a oleaginous injections and suspensions, can interrupt the normal flow of blood
and their use is generally restricted to other than intravenous administration.
 The onset and duration of action of drug may be somewhat controlled by its chemical form, physical state of
injection (solution or suspension), and the vehicle.
 Drugs that are soluble in body fluid have most rapid absorption and onset of action. Thus they have rapid onset
action in aqueous solutions than in oleaginous solution.
 Drugs in aqueous suspension are also more rapid acting than in oleaginous suspension due to greater miscibility
of aqueous preparation with body fluid after injection and more rapid contact of drug particles with body fluids.
 Often times long action is desired to reduce the frequency of injections. These long acting injections are called
repository or depot preparations.
 PREPARATION CRITERIA'S FOR PARENTERALS
 Solvents or Vehicles must meet special purity and other standards ensuring their safety by injection.
 The use of added substances, such as buffers, stabilizers, and antimicrobial preservatives, fall under specific
guidelines of use and are restricted in certain parenteral products.
 Parenteral products are always sterilized, meet sterility standards, and must be pyrogen free.
 Parenterals solutions must meet compendial standards for particulate matter.
 Parenteral products must be prepared in environmentally controlled areas, under strict sanitation standards , and
by personnel specially trained and clothed to maintain the sanitation standards.
 Parenteral products are packaged in special hermetic containers of specific and high quality. Special quality
control procedures are used to ensure hermetic seal and sterile condition.
 Each container of an injection is filled to a volume in slight excess of labeled volume to be withdrawn. This
overfill permits ease of withdrawal and administration of the labeled volumes.
 The volume of injection permitted in multi-dose containers is restricted as the types of containers (single or
multiple-dose) that may be used for certain injections.
 Specific labelling regulations apply to injections.
 Sterile powders intended for solution or suspension immediately prior to injection are frequently packaged as
lyophilized or freeze-dried powders to permit ease of solution or suspension upon the addition of solvent or
vehicle.
 Formulation of Parenteral Products
 In the preparation of parenteral products, the following substances are added to make a stable preparation:

1. The active drug

2. Vehicles
 Aqueous vehicle (e.g. water for injection, water for injection free from CO2 )
 Non-aqueous vehicle (e.g. Ethyl alcohol, propylene glycol, almond oil)
3. Adjuvants
 Solubilizing agents (e.g. Tweens & polysorbates)
 Stabilizers & antioxidants (e.g. thiourea, ascorbic acid, tocopherol)
 Buffering agents (e.g. citric acid, sodium citrate)
 Antibacterial agents (e.g. benzyl alcohol, metacresol, phenol)
 Chelating agents (e.g. EDTA)
 Suspending, emulsifying & wetting agents (e.g. MC, CMC)
 Tonicity factor (e.g. sodium chloride, dextrose)
 Disadvantages of water miscible solvents: Large amounts of mixed solvent systems may
be irritating or toxic
 Disadvantages of oily injections
 May be too viscous in cold weather for administration without warming.
 They often cause pain on injection.
 They must be injected with great care to avoid accidental I.V. injection which could lead
to thrombosis.
 May cause sensitivity reactions in some patients
 Used for Intramuscular use only
 AQUEOUS VEHICLE
1. Water For Injection (WFI) USP
2. Sterile Water for Injection (WFI)
3. Bacteriostatic WFI
1. WATER FOR INJECTION (WFI) USP:
 Highly purified water used as a vehicle for injective preparations which will be subsequently
sterilized.
 Pyrogen free
 USP requirement include not more than 10 parts per million of total solids.
 pH of 5.0 – 7.0 .
 Stored at 5oC or 60oC - 90oC
 WFI may be prepared by either distillation or reverse osmosis.
 Stored in chemically resistant tank.
 Must be used within 24 hours
 Sterilized to produce sterile WFI
 The water should be collected in sterile and pyrogen free containers.
 The containers are usually glass or glass lined.
2. STERILE WFI
 It is sterilized WFI
 Pyrogen free and have allowable endotoxin level not more than 0.25 USP endotoxin units per millilitre.
 Contain NO antimicrobial agent or other added substances.
 May contain slightly higher level of total solids than the WFI (leaching of glass constituents during
sterilization).
 This water is intended to be used as a solvent, vehicle or diluted asceptically for already sterilized and
packaged injectable medications.
 Packaged in single container ≤ 1-liter size.
 Used as a vehicle for injectable that are already sterilized and packaged (e.g in Vials)
 Single dose container for intravenous administration after addition of a suitable solute.
 It may also be used as a dispensing container for diluent use.
 The pH is 5.5 (5.0 to 7.0)
 The 1-L bottles cannot be administered intravenously because they have no tonicity. Thus used for
reconstitution of many antibiotics.
3. BACTERIOSTATIC WFI

 It is SWFI containing one or more suitable antimicrobial agents.

 It is packed in prefilled syringes or in vials containing not more than 30 mL of the water.
 The containers should be labelled with names and proportion of antimicrobial agents.
 Theoretically , presence of the bacteriostatic agent gives flexibility for multiple dose vials.
 If the first person withdraw the medication inadvertently contaminates the vial contents, the preservative will
destroy the microorganism, although there has been debate on how much protection the antimicrobial agent can
provide in a multiple-dose vial.
 As it contains antimicrobial agents, it is only used for parenteral that are administered in small volumes.
 Its use in parenteral administered in large volume is restricted, by excessive and perhaps toxic amounts of
antimicrobial agents that would be injected along with medications.
 Generally if more than 5 mL of solvent is required , sterile WFI rather than bacteriostatic WFI is preferred.
 Prior use of bacteriostatic WFI, chemical compatibility of bacteriostatic agent or agents with particular medicinal
agents should be given.
 PRETREATMENT OF WATER
 The water for injection is most commonly used solvent.
 Water for injection is the water prepared by reverse osmosis or distillation and contains no added substances.
 The water must be adequately pre-treated to ensure the uniformity and to promote constant quality and high
efficiency.
 Some of the important elements include:
1. Chlorination or treatment with ozone to suppress the microbial growth throughout the system.
2. Prefiltration through depth filters to remove ion and any suspended matter
3. Injecting a flocculating agent to remove the suspending agents, if any.
4. Water softening by ion-exchange to remove alkaline earth metals, calcium and magnesium, and thus
minimize the formation of scale deposits.
5. pH adjustment to 6.0-6.5 to reduce scale deposits.
6. Deionization by ion exchange resins to removal of ions from feed water.
7. Activated carbon beds for removal of chlorine and organics and then treatment with UV radiation to
suppress the microbial growth.
 REVERSE OSMOSIS (RO)

 This is defined as a process for the separation

of solutes from the water by applying pressure
on more concentrated solution in contact with
semi permeable membrane to give less
concentrated solution.
 The solutes may be charged (ions) or
essentially neutral (organics) .
 Each is excluded or removed by different
mechanisms.
 Charged particles are repelled or excluded due
to interfacial tension at the water membrane
interface.
 Organics are excluded by sieve mechanism so that size and molecular weight are important attributes.

 The higher the size or molecular weight of a substance, the most efficiently it is excluded.

 Thus virus, bacteria, and pyrogen are removed by reverse osmosis.

 The overall system primarily depends on the composition of feed water and the quality of the final water
desired.

 In addition to RO unit, other type of systems may include chlorinators, flocculating agents, filters, water
softeners, heat exchangers, active carbon beds, decarbonators, deionizers etc.,
 DISTILLATION

 The action of purifying a liquid by a process of heating and cooling.

 The process of removal of impurities from the liquid by continuous heating above 100 degrees and at
atmospheric pressure cooling simultaneously.
 This aids in killing the living microorganisms.
 Prior to distillation, water used as source for WFI should be done with pre-treatment
 Perfect phase change would leave all the impurities behind producing pure water vapour.
 After this the vapour is condensed to liquid water.
 It is maintained at pressure greater than the water of lower purity.
 The objective is to control the number of organisms per unit volume of water used for final rinses of
equipment and containers.
 After distillation it is filtered and stored in a chemical resistant stainless steel tank at a cold temperature around
5°C or at an elevated temperature between 65-85°C to inhibit the microbial growth and pyrogen formation.
Antioxidants

 Many drugs in aqueous solutions are easily degraded by oxidation.

 Small-volume parenteral products of these drugs often contain an antioxidant.

 Bisulphites and meta bisulphites (0.1-0.15% w/v) are commonly used antioxidants in aqueous injections.

 Antioxidants must be carefully selected for use in injections to avoid interaction with the drug.

 Antioxidants have a lower oxidation potential than the drug and so are either preferentially oxidized or block
oxidative chain reactions.

 Reducing agent: Ascorbic acid, sodium bisulfite, sodium metabisulfite and Thiourea.

 Synergists: Ascorbic acid, citric acid, citraconic acid, phosphoric acid, Tartaric acid

 Blocking agents : Ascorbic acid esters, Butyl hydroxytoulene (BHT), Tocophenols

 Chelating agents: Ethylenediaminetetraacetic acid salts.

 Solute
 Physical and Chemical purity of solutes used for sterile preparations must also be exceptional.
 Obviously , contaminants entering a product with a solute have the same effect as if they entered via the
vehicle.
 Even small traces of contaminants may be detrimental to products, necessitating purification of the solute.
 Additionally solute should be free from microbial and pyrogenic contamination.
 This entails not only proper quality of the chemical as procured but storage conditions designed to prevent
contamination, particularly after a container has been opened.
 Preferably, production lots should be designed to use the entire contents of packages of chemicals whenever
possible.
 Eg. Sucrose, Mannitol, Lactose.
 Antimicrobial agents
 A suitable preservative system is required in all multiple-dose parenteral products to inhibit the growth of
microorganisms accidently introduced during withdrawal of individual doses.
 Preservatives may be added to single-dose parenterals products that are not terminally sterilized as a sterility
assurance measures: i.e.., to prevent growth of any micro-organism that could be introduced if there were any
inadvertent breach of asepsis during filling operations.
 The use of preservative in single-dose parenteral products must weighed against the need to develop
formulations that are acceptable to regulatory bodies worldwide.
 The use of preservative is a difficult challenge, as its wide range of viewpoints concerning which preservatives
are acceptable and when it is appropriate to include them in formulation.
 Partly due to this there is trend in parenteral product development to eliminate preservatives wherever it is
practical to do so.
 This may require added measures in manufacturing to improve sterility assurance, such as using barrier
technology to provide positive separation of personnel from product during aseptic filling and transfer steps.
 The formulation scientist must be aware of interactions between preservatives and other components of a
formulation that could compromise the efficacy of the preservative.
 E.g. Proteins can bind thimerosal, reducing preservative efficacy.
 Partitioning of preservative into a micellar phase or an oil phase (in an emulsion) can also reduce the effective
concentration of preservative available for bactericidal or bacteriostatic action.
 Preservative efficacy testing should be done on the proposed formulation to assure an effective preservative
concentration.
 Preservatives have incompatibilities with rubber closures and other packaging components, particularly
polymeric materials.
 The product with selected microorganisms to measure bacteriostatic or bactericidal activity is necessary,
including evaluation of efficacy as a function of time throughout the anticipated shelf life of the product.
 More subtle effects of preservatives on injectable formulations are possible.
 E.g. Formulation of insulin: As it’s a multiple-dose vial thus individual dosage may vary among patients.
 Preservation of zinc insulin with phenol causes physical instability of suspension, whereas methyl paraben does
not have. However the presence of phenol is required for obtaining protamine insulin crystals.
 Buffers
 Many drugs require a certain pH range to maintain product stability.
 Solubility of drug may be strongly dependent on the pH of the solution.
 The product attains its maximum or minimum solubility when it is buffered whenever desired.

 Parenteral products should be formulated to possess sufficient buffer capacity to maintain proper product pH.

 Factors that influence pH include product degradation, container and stopper effects, diffusion of gases through
the closure and the effect of gases in the product or in headspace.
 However the buffer capacity of formulation must be readily overcome by the biological fluids: thus, the
concentration and ratios of buffer ingredients must be carefully selected.
 Buffer systems for parenterals consists of either a weak base and the salt of weak base or a weak acid and salt of
weak acid.
 Buffer systems commonly used for injectable products are acetates, citrates and phosphates.
 Amino acids are being increasingly used as buffers, especially for polypeptide injectable.
 Chelating Agents

 Chelating agents are added to complex and, thereby, inactivate metals such as copper, iron, and
zinc that generally catalyze oxidative degradation of drug molecules.

 Sources of metal contamination include raw material impurities; solvents, such as water rubber
stoppers, and containers; and equipment employed in manufacturing process.

 The most widely used chelating agents are edetate disodium derivatives and salts.

 Citric and tartaric acids are also employed as chelating agents.

 Inert Gases

 Another means of enhancing the product integrity of oxygen-sensitive medicaments is by displacing the air in
the solution with nitrogen or argon.

 This technique may be made more effective by first purging with nitrogen or boiling the water to reduce
dissolved oxygen.

 The container is also purged with nitrogen or argon before filling and may also be topped off with the gas
before sealing.

 Glass-seal ampoules provide the most impervious barrier for gas transmission.

 A butyl rubber stock is used with rubber-stoppered products that are sensitive to oxygen because it provides
better resistance to gas permeation than other rubber stocks.
 Solubilizing Agents and Surfactants

 Drug solubility can be increased by use of solubilizing agents e.g. lecithin, PEG, PG, Ethyl alcohol etc. and by
nonaqueous solvents or mixed solvent systems, to be discussed shortly.

 When using solubilizing agents, the formulator must consider their effect on the safety and stability of drugs.

 A surfactant is a surface active agent that is used to disperse a water-insoluble drug as a colloidal dispersion.

 Surfactants are used for wetting and to prevent crystal growth in a suspension.

 Surfactants are used quite extensively in parenteral suspensions for wetting powders and to provide acceptable
syringability.

 They are also used in emulsion and for solubilizing steroids and fat soluble vitamins.
 Tonicity Adjustment Agent

 It is important that injectable solutions that are to be given intravenously are isotonic, or nearly so.

 Because of osmotic pressure changes and the resultant exchange of ionic species across RBC membranes,
nonisotonic solutions, particularly if given in quantities more than 100 mL., can cause hemolysis or crenation of
RBC (owing to hypotonic or hypertonic solutions, respectively.)

 Dextrose, sodium chloride, or potassium chloride is commonly used to achieve isotonicity in a parenteral formula.
 Protectants

 A protectant is a substance that is added to a formulation to protect against loss of activity caused by some stress that is
introduced by the manufacturing process or to prevent loss of active ingredients by adsorption to process or to primary
packaging materials .

 Protectants are used primarily in protein formulations, liposomal formulations and vaccines.

 E.g. cryoprotectants and lyoprotectants are used to inhibit loss of integrity of API resulting from freezing and drying.

 Compounds that provide cryoprotection are not necessarily the same as those that provide lyoprotection.

 PEG protects lactate dehydrogenase and phosphofructokinase from damage by freeze drying.

 Sucrose and trehalose are effectively lyoprotectants for both proteins.

 These also markedly improve the stability of proteins against inactivation by thermal denaturation.

 Another type of protectant is used to prevent loss of API-again, usually a protein and usually present at a very low
concentration-by adsorption to material equipment in manufacturing process or components of primary packaging.
 PACKAGING
Containers
 Containers components for parenteral products must be considered an integral part of product because they can
dramatically affect product stability, potency, toxicity, and safety.
 Parenteral dosage forms, especially solutions requires more detailed evaluation of packaging components for
product compatibility and stability than do other pharmaceutical dosage forms.
 Common container components in direct contact with product include glass, rubber, plastic and stainless
steel(needles), all of which may react with drugs.
 Maintenance of microbiological purity and product stability , adaptability to production operations and
inspections, resistance to breakage and leakage and convenience of clinical use are factors that must be evaluated
when selecting the containers.
 Parenteral packaging includes ampoules, rubber-stoppered vials and bottles, plastic bags and bottles, glass, and
plastic syringes, and syringe-vial combinations.
1. Glass Containers
 Glass is a readily available economical material which is Relatively inert, thus giving excellent product/pack
compatibility, and provides good product presentation (clarity, sparkle, design) together with good product
identification.
 Glass earlier suffered some limitations associated with the production process and difficulties in finding a
satisfactory closure.
 Today blown glass containers can be made at speeds of over 200 per minute with range of neck finishes that are
suitable for many types of closure.
 In spite of their weight and fragility, glass containers can be handled at high speed on production lines.
 The various pharmacopoeia define the types of glass used for packaging pharmaceutical preparation as follows:
1. Type I Neutral or borosilicate
2. Type II Soda glass with a surface treatment
3. Type III Soda glass of limited alkalinity
4. NP Soda glass (non-parenteral usage)
 Neutral glass is more expensive and is more difficult to process.
 It is harder, more resistant to thermal shock, and durable, hence any likelihood of surface erosion is considerably
reduced.
 Types I, II and III are intended for parenteral preparations and type N.P. for oral, topical products and other
commercial purposes.
 Type I is used for most injections and for water for injection.
 Types I and II may be used for infusion fluids, blood and plasma. Because these preparations require large
volume containers, treated soda­lime glass is allowed as a less costly alternative to boro-silicate.
 Types I and III may be used for most of the oily injections. Type III is specified for thiopentone sodium.
 To avoid the deleterious effect of light, coloured glass containers could be used.
 Glass can be coloured as follows:
Carbon and sulfur or iron and manganese Amber
Compounds of cadmium and sulfur Yellow
Cobalt oxide or cupric oxide Blue
2. Plastics
"Plastic" is a term used generally to describe a variety of compounds of high molecular weight that can be molded to shape , hardness ,
and clarity .
Some common plastic materials used in medical devices are listed below :
1. Polyethylene. Various densities are available (low, medium, high). It is relatively inert, opaque material containing no plasticizer,
constituting a common ingredient of plastic syringes
2. Polypropylene. Similar to polyethylene, being relatively inert, available in many grades, and autoclavable. It is a common ingredient
of plastic syringes.
3. Polyvinyl chloride. Available in a variety of formulation to produce relatively clear, autoclavable container. When 30% to 40% of a
phthalate ester is added to formula, this product can be flexible, Polyvinyl chloride formulations are used to manufacture plastic I.V.
bags. All l.V. tubing administration sets are polyvinyl chloride formulations.
4. Polystyrene. An inexpensive, rigid clear type of plastic material; however, being not very inert, wilt react with paraldehyde and other
materials. It has a low melting temperature and cannot be heat sterilized.
5. Nylon. A stable inert and generally opaque material, can be made and used where hardness is necessary (e.g.. I. v sets, filters in blood
sets).
6. Polymethylmethacrylate (Lucite). A relatively expensive, stable, hard material used to make needle adaptors on l. v. sets.
7. Polyolefins (polyethylene and polypropylene). A mixture of two compounds produces a rigid or semi-rigid formulation containing no
plasticizer.
 Plastic devices used for parenteral medical practice include:
1. Disposable syringes (polyethylene, polypropylene, polycar-bonate)
2. I.V. solution administration sets (polyvinyl chloride (PVC))
3. Plastic I.V. catheters (Teflon, polypropylene)
4. Blood containers (polyvinyl chloride)
5. I.V. solution containers (polyvinyl chloride)
6. Irrigating solutions (polyolefins, polyethylene, polypropylene)
 A common I.V. administration set may combine a variety of plastic components tailored to suit a particular
need.
 For example, an administration set contains a nylon spike, a Lucite Y- site, a polyvinyl chloride tube, and a
polypropylene clamp.
 Plastic components may contain a variety of additives to enhance the quality desired for their use.
1. Plasticizers to give flexibility to the package.
2. Antioxidants are added to prevent discoloration.
3. Plastic devices are produced with heat and pressure which may result in the need for stabilizing agents.
4. Fillers may be added to enhance the formulation.
5. Anti static agents are sometimes needed to prevent clinging of the material.
6. Colorants may be necessary for some devices.
7. Lubricants are added to facilitate removal from the production molds
 Numerous factors are involved in considering plastic material for parenteral use;
 vapor transmission, sterilization qualities,
 texture, clarity, weight, aging, ease of production,
 ease of destruction, ultimate method of use,
 inertness, chemical reactivity of plastic material with drug, binding, leaching and.
 Probably most important, biologic safety.
 Soft, flexible plastic bags have some advantages over the traditional glass containers:-
• The most outstanding feature of this type of container is its ability to respond to normal outside atmospheric
pressure.
• The possibility of air embolism is significantly reduced in the use of flexible plastic containers.
• Flexible containers are non-breakable.
• Studies have shown that plastic I.V. containers have less particulate matter than do glass containers.
3. Rubber closures
 The basic types of polymers in rubber formulations are saturated and unsaturated elastomers or a combination of
the two. The following classification lists most of the polymers utilized as parenteral closures:
 Unsaturated elastomers
1. Polyisoprene-natural or synthetic.
2. Polybutadiene
3. Styrene butadiene rubber.
4. Nitrile butadiene rubber.
5. Polychloroprene.
 Saturated elastomers
1. Copolymer of polyisobutylene and polyisoprene (butyl).
2. Ethylene propylene rubber.
3. Ethylene propylene diene rubber.
4. Silicone rubber.
 Rubber components are usually formulated from many ingredients.
In addition to the basic polymer, ingredients used might include:
 Accelerators: Amines, thiol and thiuram compounds, sulfamides, ureas
 Activators: Stearic acid, Zinc oxide. Zinc stearate. Amines, paraffin waxes.
 Vulcanizing agents: Sulfur, organic peroxides, phenolic resnis.
 Pigments: Carbon black, chromium oxide, iron oxide
 Plasticizers and lubricants (Processing aids): Paraffin, mineral oils, fatty oils, organic phosphates, phthalates.
 Reinforcing agents (filters): Aluminum and calcium silicates. .titanium dioxide, carbon black, silica, barium
sulfate.
 Production variations which may occur during the manufacture of stoppers can affect the quality and the
properties of the stopper.
 In order to maintain batch-to- batch uniformity of particular formulation the following control tests are
necessary:
A. Physical properties:
A number of physical properties of stoppers are important:-
1. Durometer:
This is a measure of the hardness of rubber. In general, a value of is a soft rubber; , average; and above 45 , hard
rubber. Higher durometer values usually mean increased coring, reduced resealability, and increased resistance to
puncturing. However, a high durometer value is needed for syringe plunger-heads.
2. Coring:
Coring is a phenomenon in which a small plug or particle of rubber is cut out of the stopper as the needle is
inserted. The rubber type, formulation, and stopper design (including thickness of target area) will influence the
coring rate.
3. Resealability:
The resealability will vary with rubber stocks. Since the stoppers must reseal to prevent contamination and leakage
it is obviously quite important that the resealability be evaluated.
4. Puncture resistance:
The pressure required to insert the needle through the closure is an important physical characteristic. Injections which
are normally administered with thin needles (23-25 gauge)must have lower puncture resistance than those
administered with needles having a larger diameter.
5. Compression set:
Some rubber deforms permanently when held under pressure. It is desirable that closure materials have good
recovery after compression to assure good sealing characteristics with the glass finish.
6. Moisture Vapor Transmission (MVT):
 MVT is an important consideration when selecting a closure for hygroscopic powders, lyophilized products, and
for products in which an inert gas is overlaid.
 MVT is inversely proportional to the thickness of the barrier. Generally, increasing the filler will decrease MVT.A
number of materials such as lacquer, plastic, or teflon have been applied to stoppers in an attempt to reduce MVT,
to retain an inert gas, or to minimize sorption and leaching.
 Although some of these materials are apparently being used satisfactorily, their main disadvantage is the
sloughing of the coating on aging and With needle penetration.
7. Tackiness:
For ease of handling it is desirable that stoppers should not stick together or clump during processing and handling.
This usually occurs when stoppers are heated during sterilization.
B. Compatibility with preparation:
 Normally if enough tests are run it will be possible.to find a closure that is compatible with the parenteral product.
The most common compatibility problem which occurs with stoppers:-
(1) the leaching of ingredients from the stopper and the reaction of these ingredients with the product. For instance,
waxes may migrate to the surface of the stopper, resulting in particulate contamination of the product.
(2) Another problem is the sorption by the closure of preservatives or other ingredients in solution.
 Due to the large variety of ingredients in most rubber formulations, it is usually quite difficult to determine which
ingredient or ingredients might be leached into the product, possibly resulting in turbidity, precipitation, etc.
 Methods of evaluation include:
1. microscopic examination of the particulate contaminant
2. evaluation of the solution or other extracts of the closure by ultraviolet or infrared spectroscopy, thin layer
chromatography, nuclear magnetic resonance, gas chromatography and mass spectroscopy.
3. Qualitative and quantitative determinations of closure ingredients from extracts of various stopper formulations,
obtained under accelerated storage conditions, using various solvents, pH conditions.