Pharmaceutical Parenteral Preparations Quiz

Sterile Pharmaceutical Preparations

• Sterile preparations include parenteral preparations, ophthalmic preparations, dialysis solutions/irrigation solutions, radiopharmaceuticals, and plasma expanders.

Parenteral Preparations

• Parenteral preparations are sterile dosage forms given outside the alimentary canal (bypassing the digestive system).
• They are administered by injection, infusion, or implantation into human or animal bodies.
• This method is used for drugs with instability in the gastrointestinal tract (GIT), drugs with poor GIT absorption, GIT irritating drugs, unconscious or uncooperative patients, rapid correction of fluid and electrolyte imbalance, and nauseated or vomiting patients.

Types of Injections

• Intramuscular (IM): Injections into muscles (5 ml).
• Intravenous (IV): Direct injection into a vein.
• Subcutaneous (SC): Injections under the skin (1.5 ml, e.g., insulin).
• Intradermal (ID): Injections into the skin dermis (e.g., allergic testing).
• Intraspinal (Intrathecal): Injection through interthecal spaces into the spinal fluid (e.g., spinal anesthesia).
• Intraperitoneal (IP): Injection into the peritoneal cavity (animal studies).

Advantages of Parenteral Preparations

• Rapid onset of action (suited for emergencies).
• Lower dose and side effects (in some cases).
• Direct delivery to specific organs.

Disadvantages of Parenteral Preparations

• Invasive and painful.
• Risk of injury from needle insertion or catheter.
• Potential for mistakes (toxic dose, improper drug, contaminants).

IV Injection vs. IV Infusion

• IV injection: Administration of small volume parenterals (SVP) medications by syringe directly into a vein.
• IV infusion: Administration of large volume parenterals (LVP) via a catheter directly into a vein.

IV Infusions

• Administered to hospitalized patients for parenteral nutrition (PN) and total parenteral nutrition (TPN).
• For correcting fluid or electrolyte imbalances.
• For administering large doses of continuous drugs (e.g., antibiotics, chemotherapy).

General Advantages of Parenteral Preparations

• Treats drugs with instability in the GIT (insulin, heparin).
• Treats drugs with poor GIT absorption (streptomycin).
• Treats GIT irritating drugs.
• Suitable for unconscious or uncooperative patients.
• Rapid correction of fluid and electrolyte imbalances.
• Faster onset of action in emergencies.
• Lower doses and fewer side effects
• Targeting specific organs.

General Limitations of Parenteral Preparations

• Invasive and painful procedures.
• Potential risk and injury from needle or catheter insertion.
• Difficult to treat mistakes in administering the drug (incorrect dosage or drug, or presence of contaminants).

Classification of Parenterals

• Pharmaceutical classification: Solutions, suspensions, emulsions, and dry powders.
• Volume-based classification: Large volume parenterals (LVPs) and small volume parenterals (SVPS)

Methods of Sterilization

• Moist heat sterilization
• Dry heat sterilization
• Ionizing radiation sterilization
• Gaseous sterilization (ethylene oxide)
• Filtration (e.g., bacterial filters) (cannot be used for suspensions).

Preservation (of Parenteral preparations)

• Preservatives are added to multi-dose vials to protect from contamination during production, use, and storage.
• Not used for single-dose containers as they are discarded after opening.

Preservation (of Parenteral preparations) continued.

• Ideal preservatives must be effective against a wide range of bacteria, nontoxic in the used concentration, stable and compatible with injection components (no interactions).
• Some preservatives (e.g., benzyl alcohol) are more significant in natural and neoprine rubber, while much less in butyl rubber closures.

Commonly Used Preservatives (in Multi-dose Injections)

• Benzyl alcohol
• Chlorocresol
• Cresol
• Methyl paraben
• Propyl paraben
• Phenol
• Thiomersal

Important note: Benzalkolium chloride is not used in injections due to toxicity.

Clarity

• Parenteral solutions must be completely clear, free of foreign particles (dust, glass, fiber).
• Foreign particles can accumulate in tissues (e.g., muscle granuloma in IM injections).
• Injections directly into the bloodstream can cause fatal embolism.

Absence of Pyrogens

• Parenteral solutions must be non-pyrogenic (pyrogen free).
• Pyrogens are fever-producing endotoxins found in the outer membrane of Gram-negative bacteria.
• Pyrogens are composed of lipopolysaccharides (lipid A linked to a central polysaccharide core).

Sources of Pyrogens

• Solvents (usually water).
• Equipment.
• Packing materials.
• Raw materials.

Biological Activity of Pyrogens

• Injection of pyrogens can cause a toxic effect.
• Contamination of large volume parenterals (LVPs) can cause serious problems (e.g., fever, shock, death).
• Lipid A can affect the brain's thermoregulatory center (causing fever).
• High doses can activate the coagulation system, leading to shock and death.

Characteristics of Pyrogens

• Water-soluble.
• Non-volatile.
• Pass through bacterial filters.
• Heat-stable.

Depyrogenation

• The process of eliminating pyrogens from solvents, equipment, and raw materials.
• This is achieved through removal or inactivation.

Water Depyrogenation

• Distillation (most common method to avoid water contamination with pyrogens).
• Reverse osmosis (and filtration)
• Ultrafiltration.

Packing Materials and Equipment

• Removing pyrogens from surfaces by rinsing with non-pyrogenic water.
• Inactivation of pyrogens by dry heat at 250°C for 30 minutes (for heat-stable glass containers; not for plastic).

pH of Parenteral Products

• The ideal pH of parenteral solutions is 7.4 (neutral).
• However, certain injected drugs require different pH values due to solubility or stability issues.

Solutions for Non-Neutral SVPs

• Formulate the compound at a suitable pH for stability or solubility, using a buffer system with lower buffer capacity.
• Rapid neutralization by using natural buffer systems.
• Acceptable pH range is 4-9 (for tissues, not for IV administration).

Solutions for Non-Neutral LVPs

• IV infusions should avoid buffering systems due to their toxicity when administered in large volumes.
• IV infusions of non-neutral pH values should be injected very slowly at low infusion rates to prevent acidosis and alkalosis.
• The accepted pH range for non-neutral LVPs is 3-10.5.

Tonicity (Osmotic Pressure)

• Tonicity refers to the osmotic pressure of a solution.
• When a semi-permeable membrane separates water from an electrolyte solution, water will move to the salt compartment.
• Parenteral solutions should be isotonic to blood plasma.

Tonicity: Hypertonic Solutions

• Hypertonic solutions cause water shrinkage in red blood cells (reversible) or painful injection to tissues with nerve supply (IM and SC injections).
• Intrathecal injections should be isotonic, to prevent changes in the tonicity the cerebrospinal fluid.
• IV administrations can produce irreversible hemolysis of red blood cells (fatal).

Solutions for Hypertonic IV Solutions

• Hypertonic injection solutions can be made isotonic by dilution.
• Hypertonic solutions administered IM and SC injections can be administered (but slightly painful).
• Hypertonic IV infusions are sometimes prescribed, deliberately, in cases of high-concentration TPN nutrients (such as 25% dextrose).

Hypotonic Solutions

• Hypotonic solutions can be made isotonic by adding electrolytes like sodium chloride, or osmotic agents such as mannitol or glucose.
• The latter two can be incompatible with certain drugs.
• Parenteral solutions should be made isotonic with isotonic saline solution (0.9% NaCl).

Calculating Tonicity Adjustment

• The amount of solute needed or the dilution required can be calculated using different methods, such as the freezing point depression method, sodium chloride equivalents, molar concentrations, and serum osmolarity. (Refer to tutorials for details).

SVP vs. LVP

• This section includes a comparative table with different data points for sterile preparation types (SVP and LVP).

Components of Parenteral Products

• Container (packaging).
• Active constituent.
• Solvent.
• Additives.

Packaging Containers

• Glass ampoules.
• Rubber-stoppered vials
• Glass and plastic bottles.
• Glass and plastic syringes.
• Prefilled syringes.

Packing Materials

• Glass.
• Rubber.
• Plastic.

Ampoules

• Single-dose glass containers for small-volume parenterals (SVP).
• Glass neck is often scratched for easy breaking.
• Potential for releasing glass particles into the solution.

Vials

• Used for multi-dose and single-dose (1-100 ml) small-volume parenterals (SVP).
• Glass bottle with a rubber cap sealed with an aluminum cover.
• Rubber material: Natural or synthetic (butyl rubber).

Vials: Limitations

• Incomplete sealing of multi-dose vials.
• Air contamination.
• Release of rubber particles.
• Adsorption of injection components (e.g., preservatives).

Pre-filled Syringes

• Advantage: Overcome problems of particle release and air contamination during preparation and administration.
• Limitation: Expensive and require special machinery.

Plastic Containers for LVPs

• LVP single-dose IV infusion bottles (100-1000 ml).
• Polymer materials (polyethylene, polypropylene, or PVC) with additives (plasticizers, opacifiers).
• Advantages: Handling and transportation.
• Disadvantages: Potential leaching of some drugs from the container, adsorption of some drugs onto the containers, and low clarity/ poor visibility.

Flexible PVC vs. Semi-Rigid PE

• Flexible PVC: Absorbs some drugs (e.g., nitroglycerin).
• No need for an air tube for dispensing through bag flexibility.
• Semi-rigid PE: More compatible.
• Requires aeration for solution drainage.

Glass Bottles

• Advantages: Transparent and chemically inert, used with materials incompatible with plastic.
• Disadvantages: Fragile (breakable) during transportation.
• Need for aeration devices to avoid contamination.

Glass Bottles (Chemical Composition)

• Chemically consists of silicon dioxide + additional oxides.
• Three types:
  • Type III glass (soda lime glass): Releases alkalinity with water, useful for dry powders and non-aqueous solutions.
  • Type II glass (sulphated glass): Treated with sulfur oxide to neutralize alkalinity. Cannot be reused.
  • Type I glass (SiO2 + boron oxide): No release of alkalinity, multiple use and expensive.

Solvents for Injection

• Aqueous: Water, co-solvents.
• Non-aqueous: Oil, oily materials.

Grades of Water (for injections)

• Water for Injection (WFI): Potable water purified to remove pyrogens and impurities.
• Sterile Water for Injection (SWFI): WFI in sealed containers, sterilized.
• Bacteriostatic Water for Injection (BWFI): SWFI with bacteriostatic agent.

WFI Preparation Methods

• Distillation.
• Filtration.
• Chemical/Water softening.
• Deionization.
• pH adjustment.
• Reverse osmosis.

Co-solvents

• Water-miscible solvents mixed with water in some parenteral preparations to enhance solubility of certain drugs.
• Stabilize some drugs.
• Examples include glycerin, ethyl alcohol, propylene glycol, and PEG 300 (higher concentrations are often irritating and painful).

Non-Aqueous Solvents (Oils)

• Used to solubilize poorly water-soluble drugs (e.g., digoxin).
• Used to stabilize water-hydrolysable drugs (e.g., barbiturates).
• Can provide sustained drug release (e.g., steroids).

Major Class of Non-Aqueous Solvents

• Fixed vegetable oils (e.g., corn oil, cottonseed oil, peanut oil, sesame oil).
• Mineral oils, volatile oils and animal oils are not used for injections.

Additives in Parenteral Preps

• Antimicrobial agents
• Buffers
• Tonicity adjusting agents
• Antioxidants
• Surfactants

Antioxidants

• Added to maintain the stability of the solution.
• Preferentially oxidized themselves, to prevent oxidation of the preparation itself, during the shelf life of the product.
• Examples: Ascorbic acid, Cysteine, Sodium metabisulfite, Tocopherol.

Surfactants

• Used in parenteral suspensions to promote wetting, reduce crystal formation, and ensure good syringeability.
• Also used in parenteral emulsions.
• Examples are Sorbitan monooleate and polyoxyethylene sorbitan monooleate.

Production of Parenteral Solutions

• Prepared in a highly controlled sterile cleanroom environment.
• Mistakes can lead to contamination with microorganisms, pyrogens, and particulate matter.
• Raw materials, personnel, and the production area itself must be meticulously clean

Production: Raw Materials

• Special grades of raw materials (pyrogen-free) are used for preparations.

Production: Personnel

• Personnel must undergo specialized training in aseptic techniques.
• Maintaining strict hygiene and wearing special clothing.

Production: Production Area

• Sterile rooms fitted with laminar flow hoods and HEPA filters.
• Air is filtered to remove particles >0.3 µm.

Note: Laminar flow/HEPA filters

• Maintains a sterile environment by filtering out particles and microbial contaminants (it is not a sterilization method).
• Crucial for IV admixtures (sterile products added to an IV fluid).
• Administration of IV admixtures should occur in an aseptic environment to preserve sterility, clarity, and pyrogen-free status.

Quality Control Testing and Evaluation (BP)

• Three levels of testing to assess sterile preparations:
  • Tests for containers
  • Tests for the whole batch
  • Tests for samples within the batch.

Container Tests

• Glass containers: Surface and powdered glass alkalinity tests.
• Plastic containers: Leaching tests examining for color, pH, turbidity, UV absorbance, and reducing substances; biological testing on mice for toxicity.
• Rubber closures: Tests for releasing materials and permeability. Other tests include resealing and fragmentation tests.

Whole Batch Tests

• Leaker test: Testing for proper sealing by immersing ampoules in a methylene blue solution after autoclaving.
• Clarity test: Visual inspection for the presence of particles over 50 µm.

Samples tests (Within Batch)

• Sterility tests.
• Pyrogen tests (rabbit pyrogen test or LAL test).
• Extractable volume test.
• Clarity test (sub-visible particles, using direct measurement or microscopic counting).