STERILE PRODUCTS – LACHMANN

NOTES BY ZUBIA

INTRODUCTION
1. Definition of Sterile Products: Sterile products are dosage forms of therapeutic agents free of viable
microorganisms. Includes parenteral, ophthalmic, and irrigating preparations.

2. Uniqueness of Parenteral Products: Parenteral products are distinct as they are injected through the
skin or mucous membranes. Must be free from microbial contamination of all types (physical, chemical
or microbiologic origin), toxic components, and possess high purity.

3. Routes of Administration for Parenteral Preparations: intravenous, intramuscular, subcutaneous,

intradermal, and intraperitoneal.

4. Drug Absorption and Availability:

1. Intravascular Injection:

o Immediate drug availability without the need for absorption.

o No permeation through blood vessel or tissue cell walls is required.

2. Other Routes of Administration:

 Absorption is necessary for routes other than intravascular.

 Permeation through blood vessel and tissue cell walls is required.
 Passive diffusion is the common mechanism.
 Favorable when the drug has both lipophilic and hydrophilic properties, with lipophilicity
being predominant.

3. Factors Affecting Absorption:

 Non-vascular injections are influenced by:

o Size and number of blood vessels supplying the tissue.
o Movement (exercise) of the tissue post-injection.
o Physical and chemical properties of the drug.
o Characteristics of the dosage form (solution, suspension, or emulsion).
o Nature of the vehicle and its pH.

4. Physiological Effects in Circulating Blood:

 Physiological effect influenced by:

o Distribution throughout the body.
o Degree of binding to plasma proteins.
o Rate of elimination via hepatic metabolism and/or renal excretion.

5. Intravenous and Intraspinal Preparations:

 1. Intravenous and Intraspinal Preparations:

 Primarily administered as aqueous solutions.

 Emulsions are used cautiously with controlled particle size, especially in intravenous
administration to avoid capillary blockage in fine brain capillaries.
 Intraspinal medication requires the use of pure solutions due to nerve tissue sensitivity.

2. Preparations for Other Routes (Intramuscular, Subcutaneous, Intradermal):

 Administered as solutions, suspensions, or emulsions.

 Solid pellets can be implanted subcutaneously or intramuscularly.

3. Variety of Vehicles:

 Vehicles range from Water for Injection to glycols to fixed oils.

4. Tissue Irritation Considerations:

 Care is taken to avoid undue tissue irritation.

 Mild local irritation is permissible at injection sites.

5. Specialized Parenteral Routes and Formulation Constraints:

 Detailed information on specialized parenteral routes, volume, types of medication

administered, and formulation constraints is summarized in Table 23.1.

7. Summary of Formulation Development for Parenteral Products:

1. Influence on Therapeutic Effect:

 The nature of a preparation significantly affects:

o Rapidity of onset of therapeutic effect.
o Duration of the effect.
o Form of the absorption pattern.

2. Integration with Administration:

 Formulation development for a parenteral product must be carefully integrated with its
intended administration in a patient.

3. Considerations in Formulation Development:

 Chemical and physical properties of the drug must be determined.

 Interaction with desired excipients needs to be studied.
 Effects of each step of the process on the stability of the product must be thoroughly studied
and understood

8. Standards for Ophthalmic Preparations and Irrigating Solutions:

1. Ophthalmic Preparations:

 Not introduced into internal body cavities but in contact with sensitive eye tissues.
  Similar standards as parenteral solutions are required due to the high sensitivity of eye tissues to
contamination.

2. Irrigating Solutions:

 Must meet the same standards as parenteral solutions.

 During irrigation procedures, substantial amounts can enter the bloodstream directly through
open blood vessels of wounds or abraded mucous membranes.
 Characteristics and standards for the production of large-volume parenteral solutions are
applicable to irrigating solutions.

EFFECT OF ROUTE OF ADMINISTRATION

Formulation Considerations Based on Route of Administration:

1. Intracutaneous Injections:
a. Volume rarely exceeds 0.2 ml due to small and compact tissue volume.
b. Absorption is slow because of the lack of blood vessels.
2. Subcutaneous Injections:
a. Volumes of 1 ml or less are common.
b. Larger volumes, occasionally exceeding 2 ml, may be injected intramuscularly.
3. Intraspinal Injections:
a. Volumes of 10 ml or less are acceptable.
b. Larger volumes are safe only through the intravenous route, with careful administration
rate control.
4. Practical Considerations:
a. Syringe administration is inconvenient for volumes exceeding 20 ml.
b. Setting up an infusion unit is usually not practical for volumes less than 250 ml.

Isotonicity and Administration Characteristics:

1. Intraspinal Injections:
a. Isotonicity is crucial due to slow cerebrospinal fluid circulation.
b. Disturbances of osmotic pressure can quickly lead to headache and vomiting.
2. Intracutaneous Injections:
a. Non-isotonic solutions may cause false signs of irritation.
b. Given mostly for diagnostic purposes.
c. Isotonicity is preferable for patient comfort but not essential for subcutaneous (SC) and
intramuscular (IM) injections.
3. Intramuscular Injections:
a. Slightly hypertonic solutions may enhance rapid drug absorption by causing local
effusion of tissue fluids.
4. Intravenous Fluids:
a. Typically, should be isotonic.
 b. Slow administration of a paratonic solution may be safe if rapid dilution with the blood
occurs.
5. Intravenous Drug Administration:
a. Only solutions of drugs in water are suitable.
b. Suspensions are not given due to the risk of small blood vessel blockage.
6. Subcutaneous Administration:
a. Aqueous or oleaginous suspensions and oleaginous solutions are normally avoided due
to pain and irritation.
b. Muscle tissue is more tolerant, making it suitable for administration of oils and
suspended particles.

Drug Release from Muscle Depot:

1. Depot Formation:
a. Administration deep into muscle tissue results in a depot (pool) of the drug at the
injection site.
2. Rate of Release:
a. The rate of drug release is determined by the characteristics of the formulation.
3. Solvent Influence:
a. Whether the solvent is aqueous or oleaginous affects the rate of absorption.
b. Oleaginous solutions are usually absorbed more slowly.
4. Viscosity Effect:
a. Increasing the viscosity of solutions slows absorption. Example:

Gelatin or polyvinylpyrrolidone in water and aluminum monostearate in oils can slow

absorption.

5. Modification of Drug Molecule:

a. Modifying the drug molecule (e.g., forming esters or salts) allows the production of
stable suspensions.
b. Stable suspensions lead to a significant reduction in the rate of drug absorption from the
depot.
6. Formulation Modifications:
a. Utilizing various modifications in the formulation allows for the retardation of the rate
at which a drug is released from a depot.

Formulation of Ophthalmic Preparations:

1. Similarity to Parenteral Solutions:

a. Ophthalmic preparations are formulated similarly to parenteral solutions.
2. Sensitivity to Irritation:
a. The eye is highly sensitive to irritation; thus, formulations aim to minimize irritation.
3. Preference for Aqueous Solutions:
a. Normally, clean aqueous solutions are preferable for ophthalmic use.
4. Use of Suspensions:
a. Suspensions of solids are used when therapeutic need overrides the need to avoid
irritation, e.g., corticosteroid suspensions.
 5. Particle Concentration and Sensation:
a. A foreign body sensation increases as the concentration of suspended particles
approaches 5%, regardless of size.
6. Introduction to Formulation of Parenteral Dosage Forms:
a. The discussion introduces students to the formulation of parenteral dosage forms.
7. Dynamic Field:
a. The field is continuously changing as research pharmacists develop new and improved
formulation aids and techniques.

Sterile Product Processing:

1. Nature of Sterile Product: Most frequently solutions or suspensions, but can also be solid pellets
for tissue implantation.
2. Contamination Control: Controlling the process to minimize contamination is relatively easier
for small quantities but becomes more challenging as the quantity increases.
3. Specialized Area in Pharmaceutical Processing: The preparation of sterile products is a highly
specialized area in pharmaceutical processing.
4. Challenges with Increasing Quantity: As the quantity of product increases, controlling the
process to prevent contamination becomes more challenging.
5. High Standards and Process Control: High standards and superior process control are crucial in
sterile product preparation.
6. Organizational Divisions: Divisions responsible for sterile product preparation: product
development, production, packaging, and control.

FORMULATIONS
Ophthalmic 1. Similarities with Parenterals:
Preparations a. Products instilled into the eye share similarities with parenterals,
Formulation: necessitating similar characteristics.
2. Formulation Requirements:
a. Stable, therapeutically-active ophthalmic preparations require high
purity, freedom from chemical, physical, and microbial contaminants.
3. Buffering and Additives:
a. Buffers are often needed to stabilize the pH.
b. Additives are used to render the product isotonic or nearly so.
c. Stabilizers, such as antioxidants, are added when appropriate for specific
ingredients.
4. Complexity of Preparations:
a. Preparations for larger quantities, like eye irrigants or devices such as
contact lenses, are usually relatively uncomplicated solutions similar to
large-volume parenterals.
5. Critical Characteristic - Pyrogens:
a. Freedom from pyrogens is not as critical for ophthalmics since pyrogens
are not absorbed systemically from the eye.
b. However, their absence is important as they indicate a microbiologically
clean process.
6. High freedom from pyrogens:
 only 10% remaining is acceptable, pyrogens are not absorbed through ocular
cavity (cul de sac).
7. Ocursert:
A sustained-release pellet tablet is placed in the eyesac to provide a
controlled and prolonged release of the drug. Additionally, ocular inserts or
lenses, designed as solid dosage forms, are positioned on the iris. These
inserts may contain a compact ring of the drug, ensuring a sustained and
controlled delivery to the ocular tissues. This innovative approach aims to
enhance drug efficacy and convenience for ocular administration.
Freeze-Dried 1. Aqueous Solutions for Freeze-Drying:
Products a. Solutions intended for freeze-drying must be aqueous, as the drying
process involves water removal by sublimation.
2. Stability during Processing:
a. Stability issues related to the aqueous system are practically nonexistent
during the brief period of processing.
3. Formulation Considerations:
a. Formulation must consider the characteristics of the solid residue (cake)
after drying and those needed after reconstitution for use.
b. Additional substances are often required to impart desired
characteristics, as the drug alone may not be sufficient.
4. Desired Characteristics of a Good Cake:
a. Uniform color and texture.
b. A supporting matrix of solids to maintain the original volume after
drying.
c. Sufficient strength to prevent crumbling during storage.
5. Role of Solids in the Solution:
a. Nature and amount of solids influence the eutectic temperature of the
frozen solution, the rate of thermal and vapor transfer during drying, and
the rate of reconstitution.
6. Percentage of Solids in Frozen Plug:
a. Typically between 2% and 25%.
7. Best Salts for Characteristics:
a. Monobasic and dibasic sodium phosphates are effective for uniform
crystal size, color, texture, physical strength, and rapid reconstitution.
b. Sodium chloride, when used alone, may lead to volume shrinkage and a
crusty, crumbly appearance.
8. Use of Organic Substances:
a. Mannitol, sorbitol, sucrose, and gelatin can be used but require careful
heating to avoid cake discoloration through charring.
9. Avoidance of Volatile Substances:
a. Formulation substances must not be volatile during drying; antibacterial
agents like phenol, chlorobutanol, and benzyl alcohol are avoided.

Long-Acting 1. Objective of Long-Acting Formulations:

Parenteral a. Designed to provide slow, constant, and sustained release of a drug over
Drug an extended period, aiming to replace continuous intravenous infusion.
Formulations: 2. Depot Dosage Forms:
a. Rarely achieving the ideal, extensive research has led to depot dosage
 forms that approach the desired goal.
3. Dissolution-Controlled Depot Formulation:
a. Rate of drug absorption controlled by slow dissolution of drug particles.
b. Common approach involves forming drug salts with very low aqueous
solubility.
c. Control of particle size contributes to slow dissolution.
d. Suspension of drug particles in vegetable oils, especially when gelled
with substances like aluminum monostearate, leads to prolonged
absorption rates.
4. Adsorbent-Binding Depot Formulation:
a. Drug molecules bind to adsorbents, and only the free portion in
equilibrium with the bound portion can be absorbed.
b. As drug is absorbed, a shift in equilibrium occurs, slowly releasing the
drug from the bound state.
c. Example: Binding of vaccines to aluminum hydroxide gel for sustained
release.
5. Encapsulation-Type Depot Formulation:
a. Biodegradable or bioabsorbable macromolecules (e.g., gelatin,
phospholipids) act as a diffusion matrix for the drug.
b. Drug is encapsulated within the matrix, and release is controlled by
permeation out of the diffusion barrier and biodegradation of the barrier
macromolecules.
6. Esterification-Type Depot Formulation:
a. Bioerodible esters of a drug are synthesized, forming a reservoir of drug
at the injection site.
b. Drug absorption is controlled by partitioning of drug esters from the
reservoir to tissue fluid and the rate at which the drug ester regenerates
the active drug molecule.
c. Esterified drugs are often dissolved or suspended in oleaginous vehicles,
further slowing release.

Suspensions 1. Solids Content:

a. Solids content in parenteral suspensions typically ranges from 0.5% to
5%, reaching up to 30% in certain antibiotic preparations.
2. Viscosity and Syringeability:
a. The amount of solids and the nature of the vehicle influence viscosity, a
crucial factor for syringeability (ease of passing in and out of a syringe).
b. Thixotropy, especially in oleaginous suspensions, may be used to balance
sedimentation stability during storage and syringeability during
administration.
3. Particle Size Importance:
a. Small and uniform particle size is a critical requirement to ensure slow,
uniform rates of sedimentation, predictable dissolution, and drug
release.
b. Uniform particle size minimizes crystal growth during storage, preventing
caking and changes in dissolution and drug release post-injection.
4. Particle Size Reduction Techniques:
a. Techniques like dry or wet ball milling, micropulverization, fluid energy
 grinding, ultrasonic insonation, and spray drying are employed to achieve
small, uniform particles.
5. Stabilization Challenges:
a. Solids may settle and cake over time, posing challenges in redispersion
before use.
b. Surface-active agents, including Polysorbate 80, lecithin, Emulphor EL-
620, and Pluronic F-68, aid in preparation and stabilization by reducing
interfacial tension.
6. Hydrocolloid Addition:
a. Concurrent addition of hydrocolloids like sodium carboxymethylcellulose
enhances surfactant effects, reduces surface charge, and prevents
agglomeration.
7. Protective Colloids:
a. Protective colloids such as acacia, gelatin, methylcellulose, and
polyvinylpyrrolidone are employed in formulations.
8. Viscosity Adjustment and Flocculation:
a. Viscosity may be increased with additional protective colloid or
compounds like sorbitol.
b. Flocculation of suspended particles, preventing dense cake formation,
may be necessary. Selected ions like monosodium citrate can induce
fluffy aggregates that settle rapidly but can be easily redispersed.

Emulsions 1. Formulation Challenge:

a. Principal problem in formulating parenteral emulsions is achieving and
maintaining uniform oil droplets of 1 to 5 μm in size as the internal
phase.
2. Separation and Stability:
a. Unlike suspensions, separation of phases in emulsions is less likely due to
a relatively small difference in density between oil and water.
b. Stabilization, as seen in an emulsion of natural vitamin K1 with lecithin, is
crucial.
3. Intravenous Nutrient Emulsions:
a. Examples may include 15% cottonseed oil, 4% dextrose, 1.2% lecithin,
and 0.3% oxyethyleneoxypropylene polymer as emulsifiers.
b. Dispersed phase should have droplet sizes less than 1 μm.
c. Stability to autoclaving is necessary, but elevated temperatures can lead
to coalescence and excessive shaking accelerates creaming.
4. Stabilizing Agents:
a. Small amounts of gelatin, dextran, and methylcellulose may aid in
stabilizing emulsions but are adversely affected by elevated
temperatures.
5. Challenges in Preparation:
a. Preparation of parenteral emulsions is challenging due to:
i. Strict particle size control to prevent emboli in blood vessels.
ii. Limited choice of low-toxicity emulsifiers and stabilizers.
iii. Preservation of the oil phase against rancidity.
 FORMULATION DEVELOPMENT
1. Final Objective:
a. The ultimate goal in developing a sterile product is to achieve a therapeutic effect in a
patient.
2. Formulation Objectives:
a. Formulation involves combining one or more ingredients with a medicinal agent to enhance
convenience, acceptability, or effectiveness.
b. Dispensing a drug as a sterile dry powder is rarely preferable, except when creating a stable
liquid preparation is not feasible.
3. Prime Consideration:
a. The primary focus should always be on the use of the product in a patient.
b. Physical and chemical factors should not overshadow the main consideration of the
product's application and effectiveness in a clinical setting.

Therapeutic Agent and Formulation Challenges:

1. Nature of Therapeutic Agent:
 A therapeutic agent is a chemical compound subject to the physical and chemical reactions
characteristic of its compound class.
2. Evaluation of Ingredient Combinations:
 Careful evaluation of combinations of two or more ingredients is essential to identify and
address adverse interactions.
 Formulators must use knowledge and ingenuity to overcome challenges in the formulation
of sterile products.
3. Limited Information on New Compounds:
 Information on the physical and chemical properties of a therapeutic agent, especially if it's
a new compound, may be limited.
 Basic properties like molecular weight, solubility, purity, colligative properties, and chemical
reactivity must be determined for intelligent formulation.
4. Continuous Formulation Improvement:
 Formulation is an ongoing process with continuous improvement.
 Important properties may not become evident until the product is stored or used for an
extended period.
 Only outstanding formulations, supported by extensive test documentation, can advance to
the stage of a marketed product due to FDA requirements.

Aqueous Systems for Sterile Products:

1. Prevalence of Water as a Vehicle:
 Water is the most commonly used vehicle for sterile products, mirroring its presence in
natural body fluids.
2. Quality Standards for Water:
  Water quality for sterile products is governed by the monograph on Water for Injection in
the USP.
 Total solids content is a key test, measured either gravimetrically or through conductivity.
 Conductivity measurement is often used due to its efficiency, but additional tests may be
required for contaminants other than ions.
3. Total Solids Content and Sterile Water:
 Sterile Water for Injection may have higher total solids values compared to non-sterilized
Water for Injection due to the sterilization process and container dissolution.
4. Organic Compounds in Water:
 Water for Injection should contain minimal organic compounds, as they can be toxic and
serve as nutrition for microorganisms.
 Recommended values include conductivity not exceeding 1 micromho (1 megohm) and total
organic carbon (TOC) not exceeding 500 ppm.

Non-aqueous and Mixed Solvents for Sterile Products:

1. Elimination of Water from the Vehicle:
 In certain cases, it is necessary to eliminate or reduce water in the vehicle for sterile
pharmaceutical products due to solubility issues or hydrolytic reactions.
2. Selection Criteria for Non-aqueous Solvents:
 Careful selection of non-aqueous solvents is crucial, considering factors such as non-
irritating, non-toxic, non-sensitizing properties, and absence of adverse effects on
formulation ingredients.
3. Screening Criteria for Solvents:
 Solvent screening involves evaluating physical properties (density, viscosity, miscibility, and
polarity), stability, solvent activity, and toxicity.
4. Miscible Solvents with Water:
 Solvents that are miscible with water and are often used in combination include dioxolanes,
dimethylacetamide, N-(β-hydroxyediyl)-lactamide, butylene glycol, polyethylene glycol 400
and 600, propylene glycol, glycerin, and ethyl alcohol.
5. Water-Immiscible Solvents:
 Water-immiscible solvents include fixed oils, ediyl oleate, isopropyl myristate, and benzyl
benzoate.
6. Frequently Used Non-Aqueous Solvents:
 Polyethylene glycol, propylene glycol, and fixed oils are among the frequently used non-
aqueous solvents in sterile pharmaceutical formulations.

Solvent Selection for Parenteral Formulations:

1. Preference for Aqueous Solutions:
 Parenteral therapeutic agents are preferably given as solutions, especially if aqueous, due to
physiological compatibility with body tissues and reasonably predictable biological
responses.
2. Properties of Water as a Solvent:
  Water's high dielectric constant allows the dissolution of ionizable electrolytes, and its
hydrogen bonding potential facilitates the solution of organic substances like alcohols,
aldehydes, ketones, and amines.
3. Complementary Solvents:
 The diverse properties of therapeutically active compounds, ranging from highly polar to
non-polar, require complementary solvents for achieving a solution.
4. Toxicity Considerations:
 Solvents for injections must have low toxicity to body tissues. Some solvents, while effective,
may be highly irritating. Mixed solvents, such as a combination of ethanol and water, can
sometimes address this issue.
5. Degradative Reactions:
 Compounds dissolved in water may undergo degradative reactions like hydrolysis, oxidation,
decarboxylation, and racemization. Formulations must be designed to minimize these
effects, often influenced by the pH of the solution.
6. pH Control and Antioxidants:
 Maintaining specific pH levels can mitigate degradative reactions. For example, epinephrine
solution undergoes less racemization and oxidation at a pH of 3.0 or less. Antioxidants like
sodium metabisulfite can further reduce oxidation.
7. Mixed Solvent Systems:
 The use of mixed solvent systems, combining water with other solvents, can reduce
degradative reactions. For instance, barbituric acid derivatives hydrolyze less readily in a
solution containing polyethylene glycol 400 and ethanol.
8. Anhydrous, Non-polar Vehicles:
 Anhydrous, non-polar vehicles like fixed oils can prevent certain degradative reactions, but
they come with the disadvantages of viscosity and the potential for injection pain.

Solutes for Sterile Preparations:

1. Exceptional Purity Requirement:
 Solutes used in sterile preparations must exhibit exceptional physical and chemical purity.
Contaminants entering the product through solutes can have similar detrimental effects as
contaminants in the vehicle.
2. Effect of Contaminants:
 Even small traces of contaminants in solutes can be harmful to products, emphasizing the
need for purification of solutes before their use in sterile preparations.
3. Special Parenteral Grades:
 Some substances, such as ascorbic acid and calcium gluconate, have special parenteral
grades commercially available to ensure the highest quality and purity.
4. Absence of Microbial and Pyrogenic Contamination:
 Solutes should be free from microbial and pyrogenic contamination. This requires not only
ensuring the quality of the chemical at the time of procurement but also implementing
proper storage conditions to prevent contamination, especially after opening a container.
5. Preventing Contamination During Storage:
 Storage conditions play a crucial role in preventing contamination of solutes. After a
container has been opened, efforts should be made to maintain the purity of the solute.
6. Utilizing Entire Contents:
 Preferably, production lots should be designed to use the entire contents of packages of
chemicals whenever possible, minimizing the risk of contamination associated with storing
partially used containers.

Added Substances in Sterile Preparations:

1. Essential Stability Enhancers:
 Substances added to sterile pharmaceutical products serve essential roles in enhancing their
stability. These added substances include various categories such as solubilizers,
antioxidants, chelating agents, buffers, tonicity contributors, antibacterial agents, antifungal
agents, hydrolysis inhibitors, antifoaming agents, and others designed for specialized
purposes.
2. Critical Considerations for Added Substances:
 These added substances must fulfill several critical criteria to ensure the safety, efficacy, and
stability of the product. They should be non-toxic in the administered quantity, not interfere
with the therapeutic efficacy or assay of the active therapeutic compound, and remain
active throughout the useful life of the product.
3. Careful Selection and Evaluation:
 The selection of added substances requires careful consideration, and their effects on the
entire formulation must be thoroughly evaluated. An extensive review of excipients used in
parenteral products provides detailed information on these substances.
4. Commonly Used Excipients:
 Table 23.2 provides a list of commonly used excipients in commercial parenteral products,
offering an overview of the substances employed for various purposes.
5. Antibacterial Agents:
 Multiple-dose vials and products sterilized by marginal processes often include antibacterial
agents in bacteriostatic concentration. The inclusion of antibacterial agents is crucial to
prevent microbial contamination during product use.
6. Antioxidants:
 Antioxidants play a significant role in protecting therapeutic agents susceptible to oxidation,
especially during thermal sterilization. They may function by preferential oxidation, blocking
oxidative chain reactions, acting as synergists, or complexing with catalysts. Table 23.3 lists
commonly employed antioxidants based on their mechanisms of action.
7. Oxygen Displacement:
 For products where oxygen contributes to degradative reactions, an antioxidant effect can
be achieved by displacing oxygen from contact with the product. This is typically
accomplished by saturating the liquid with nitrogen or carbon dioxide and sealing the final
container after displacing the air with the gas.

Buffers:
 Buffers are added to maintain the required pH for many sterile pharmaceutical products.
 pH changes can cause significant alterations in the rate of degradative reactions, and buffers help
stabilize the pH against various influences.
 pH changes may result from the dissolution of glass constituents, release of constituents from
rubber or plastic components, dissolution of gases, and reactions within the product.
 Buffer systems, such as acetates, citrates, and phosphates, are commonly used. Some formulations
may utilize other ingredients to act as buffer systems, reducing the total number of components.
 Buffers must be selected based on their effective range, concentration, and chemical compatibility
with the overall product.

Tonicity Contributors:

 Tonicity contributors are compounds that contribute to the isotonicity of a product, reducing pain
upon injection in areas with nerve endings.
 Adjusting tonicity is essential for enhancing patient comfort during administration.
 Common tonicity contributors include simple electrolytes like sodium chloride, sodium salts, and
non-electrolytes such as glycerin and lactose.
 Tonicity adjusters are typically added after other formulation ingredients are established, and the
osmolality of the formulation is measured.
 Isotonicity is determined based on the permeability of a living semipermeable membrane, often the
membrane enclosing red blood cells.
 Hemolytic methods, using red blood cells, are employed to test isotonicity. If the formulation is
hypotonic or hypertonic, tonicity-adjusting agents are added until isotonicity is achieved.
 For intravenous (i.v.) administration, hypertonicity values up to 360 mOsm/kg are generally
considered acceptable, but efforts should be made to achieve isotonicity for other routes of
administration.

Chelating Agents:

 Chelating agents are added to sterile pharmaceutical products to bind trace amounts of heavy
metals in a non-ionizable form.
 This prevents the catalysis of degradative changes that could be initiated by free heavy metals.
 The trisodium or calcium disodium salt of ethylenediamine tetraacetic acid, usually at a
concentration of about 0.05% (w/v), is a commonly used chelating agent.
 An example of the application of a chelating agent is in stabilizing thimerosal in poliomyelitis
vaccine. Thimerosal, a bacteriostatic agent, can be unstable in the presence of cupric ions, which are
stabilized by the chelating agent, thereby stabilizing the vaccine.
 Chelating agents may also be used to bind heavy metals extracted from rubber closures, reducing
the potential for reactions with formulation ingredients.

Inert Gases:

 Inert gases are employed to displace oxygen from a solution, reducing the likelihood of oxidative
changes in the formulation.
 They can stabilize solutions by inhibiting certain reactions. For instance, carbon dioxide saturation
can inhibit the decomposition of sodium bicarbonate injection during autoclaving, thereby
stabilizing the solution.

Protein Stabilizers:

 Various ingredients are used to stabilize proteins, both in dry and solution states.
 Serum albumin competes with therapeutic proteins for binding sites on surfaces, minimizing protein
loss caused by surface binding.
 Competitive binding agents like hetastarch are being explored as alternatives to albumin due to
concerns about viral contamination.
 Cryoprotectants and lyoprotectants, such as polyhydric alcohols (sorbitol, glycerol), amino acids
(glycine, lysine), non-reducing sugars (trehalose, sucrose), and polymers (dextran,
polyvinylpyrrolidone, methylcellulose), are used to minimize protein denaturation during freeze-
drying.
 Surface-active agents like Poloxamer 188 (Pluronic 68), polysorbate 80, and polysorbate 20 help
minimize protein aggregation at interfaces, and antioxidants, buffers, and chelating agents may be
used to stabilize proteins in solution when needed.