Pharmaceutical Classifications and Formulations Quiz

Sterile Pharmaceutical Preparations

• Sterile preparations encompass parenteral, ophthalmic, dialysis solutions, radiopharmaceuticals, and plasma expanders.

Parenteral Preparations

• Parenteral preparations are sterile dosage forms administered via injection, infusion, or implantation, bypassing the alimentary canal.
• Definition: "Parenteral preparations are sterile preparations intended for administration by injection, infusion or implantation into human or animal bodies."
• Advantages:
  • For drugs unstable in the gastrointestinal tract (GIT).
  • For drugs poorly absorbed in the GIT.
  • For irritating drugs.
  • For patients unconscious or uncooperative.
  • Rapid correction of fluid and electrolyte imbalance.
  • Nauseated and vomiting patients.
• Disadvantages:
  • Invasive
  • Painful (potentially)
  • Risk of injury from needle or catheter insertion
  • Toxic or incorrect drug injection/infusion risk
  • Difficult to treat contamination or presence of contaminants.
• Types of injections:
  • Intramuscular (IM): injection into muscles (typically 5 ml).
  • Intravenous (IV): Direct injection into veins.
  • Subcutaneous (SC): injection under the skin (e.g., insulin, typically 1.5 ml).
  • Intradermal (ID): injection into the skin dermis (e.g., allergic testing).
  • Intraspinal (intrathecal): injection via interthecal spaces into spinal fluid (e.g., spinal anesthesia).
  • Intraperitoneal (IP): injection into peritoneal cavity (mostly used in animal studies).

IV Injection vs. Infusion

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

IV Infusion Benefits

• Provides nutrition (PN, TPN) for hospitalized patients.
• Correct fluid or electrolyte imbalances.
• Administer large doses of drugs (e.g., antibiotics, chemotherapy) continuously.

General Advantages (Rational)

• The list includes drugs with GIT instability (insulin, heparin), drugs with poor GIT absorption, irritating drugs, unconscious or uncooperative patients, rapid correction of fluid/electrolyte imbalance, nauseated/vomiting patients, shorter onset of action, lower dose/side effects, and drugs targeting specific organs.

General Limitations

• Invasive and painful (potentially)
• Traumatic injury from needle/catheter insertion
• Mistakes (toxic dose/incorrect drugs/contamination) are difficult to treat.

Common Types of Injections (Advantages)

• Intravenous (IV) route: fastest method of systemic administration.
• Preferred for emergency situations.
• IV infusions (LVP) provide large doses of fluids, electrolytes, nutrients, and drugs for hospitalized/unconscious patients, treating serious GIT problems.

Administration and Precautions

• Risk of IV route: introduction of pyrogens, toxic agents, or microorganisms directly into bloodstream (irreversible).
• Solutions must be free from particles and air bubbles (embolism).
• Not suitable for suspension-based or oily injections.

Infiltration

• Breakdown or collapse of veins leading to drug leakage, edema, and tissue damage.
• Requires expertise in IV administration.

IM Injection

• Slower onset of action compared to IV, but longer duration (depot effect).
• More practical for outpatient use.
• Injection volume up to 5 ml.

Classification of Parenterals

• Pharmaceutical classification (solutions, suspensions, emulsions, dry powders).
• Volume-based classification (large-volume parenterals (LVP) versus small-volume parenterals (SVP)).

Solutions

• Aqueous solutions (IM & IV) use water or water + co-solvent based on solubility and stability (e.g., fixed oils).

Suspensions

• Used for insoluble drugs in water, given via IM.
• Prolongs effect (depot effect) by slowing drug dissolution in tissue fluids.
• Typical particle size range: 5–10 µm
• Drawbacks include caking and syringeability characteristics (clogging and foaming during administration).

Emulsions

• O/W emulsions for IM and IV injections, but parenteral IV emulsions are rare.
• Stable droplet size (below 1 µm) is crucial (emolisms).
• Example: Vitamin K.

Dry Powders

• Used for unstable drugs in solution (e.g., antibiotics).
• Reconstituted immediately before injection.
• Can be reconstituted as solution or suspension.

Volume-Based Classification

• Large volume parenterals (LVP): 100–1000 ml, no additives.
• Small volume parenterals (SVP): <100 ml, can contain additives.

Controlled Drug Delivery in Parenteral Preparations

• Increasing particle size/viscosity (using oil solutions, suspensions) ↓ drug dissolution in tissue fluids, resulting in ↓ absorption rate and sustained effect.
• Using implants (solid sterile dosage forms).
• Using less-soluble salts (e.g., Insulin-Zn).
• Using crystalline rather than amorphous form (e.g., Insulin Lente).

Insulin Lente

• Insulin zinc suspension.
• Intermediate-acting porcine or human insulin with zinc salt.
• Solid phase ratio: 7:3 (crystalline to amorphous insulin).

Assignments

• Assignment 1: Investigate various insulin formulations, noting duration and onset of action.
• Assignment 2: Collect market examples of parenteral products (dry powder, oily injections, long-acting, emulsions), including active components, doses, labels, and reconstitution methods.

Specifications of Parenteral Preparations

• Sterility: completely free of microorganisms and contaminants.
• Clarity: free of foreign particles (dust, glass fiber).
• Pyrogens: non-pyrogenic solutions needed (due to fever-producing endotoxins in gram-negative bacteria).
• Tonicity: isotonic solutions required—with the same osmotic pressure as blood plasma.
• pH: ideal pH is 7.4, however, some injected drugs require different pH values for solubility or stability.

Sterilization Methods

• Moist heat sterilization.
• Dry heat sterilization.
• Ionizing radiation sterilization.
• Gaseous sterilization (ethylene oxide).
• Filtration (bacterial filters).

Preservation

• Antimicrobial agents added to multi-dose vials.
• Protect during production, use, and storage.
• Preservatives may not be used for LVP (single-dose containers, discarded after opening).
• Preservatives optional for drugs having antimicrobial effect (e.g., methohexital sod).

Preservation (Cont.)

• Ideal preservative: Effective against a wide range of bacteria, non-toxic at the used concentration, stable, compatible with injection components (no interaction).
• Preservative uptake is more significant with natural and neoprene rubber. Butyl rubber closures have much less uptake.

Commonly Used Preservatives in Multi-Dose Injections

• Concentration (% w/v) values for preservatives listed (e.g., Benzyl alcohol, Chlorocresol, Cresol, Methyl parabens, Propyl parabens, Phenol, Thiomersal).

Clarity

• Parenteral solutions must be perfectly clear.
• Free from foreign particles (dust/glass/fiber).
• Foreign particles accumulate in tissues (e.g., IM=muscle granuloma, IV=embolism.

Absence of Pyrogens

• Parenteral solutions must be non-pyrogenic (no pyrogens).
• Pyrogens are fever-producing endotoxins (mostly found in outer membrane of gram-negative bacteria).
• Composition: lipopolysaccharides (lipid A linked to a central polysaccharide core).

Sources of Pyrogens

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

Biological Activity of Pyrogens

• Pyrogen injection can cause toxic effects.
• LVP contamination can cause serious problems:
• Lipid A affects the thermoregulatory center (fever).
• High doses activate the coagulation system, leading to shock and death.

Characteristics of Pyrogens

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

Depyrogenation

• Elimination of pyrogens from solvents, equipment, and raw materials.
• Achieved by removal or inactivation.

Water Depyrogenation

• Distillation (BP): primary method to avoid water contamination with pyrogens (non-volatile substances).
• Reverse osmosis (USP): filtration under high pressure using semi-permeable membranes that separate substances and most ions.
• Ultrafiltration: removing pyrogens from solutions.

Packing Materials and Equipment

• Removing pyrogens from surfaces using non-pyrogenic water.
• Inactivating pyrogens with dry heat (250°C/30min) for heat-stable materials (e.g. glassware).
• Plastic materials are not treated by dry heat.

pH (Cont.)

• Ideal pH of parenteral preparations is 7.4.
• Some injected drugs require different pH values due to solubility or instability.

What is the Solution? (Non-Neutral SVP Solutions)

• Formulate adjusted pH to maintain stability/solubility (buffer system, low buffering capacity).
• Allows rapid neutralization of the solution by natural buffer systems.
• Buffers used: Acetate (1-2%), phosphate (0.8-2%), and citrate (1-5%).

Non-Neutral SVP (Cont.)

• Acceptable pH range for non-neutral SVP solutions is 4–9 for tissues.
• Higher/lower values are irritant and damaging to tissues (except for IV).
• Borate buffers not allowed in parenteral formulations.

Non-Neutral LVP

• IV infusions should not contain buffering systems (comment: to prevent toxicity due to high volume).
• Large volume needs large amounts of buffer; to avoid toxicity.

Non-Neutral LVP (Cont.)

• IV infusions of non-neutral pH values should be administered slowly—with low infusion rate.
• No change in blood pH (acidosis/alkalosis) due to the large volume allowing rapid neutralization.
• Avoiding precipitation of drugs in circulation (prevent sudden changes in formulation pH).

Non-Neutral LVP (Cont.)

• Accepted pH range for non-neutral LVP: 3–10.5.
• Significant changes in blood pH (acidosis/alkalosis) can be life-threatening.

Tonicity (Osmotic Pressure)

• Semi-permeable membrane separates water from electrolyte solutions.
• Water will pass from water compartment to the salt compartment.
• Osmotic pressure: pressure required to balance water movement.

Tonicity

• Parenteral preparations should be isotonic (same osmotic pressure as blood plasma).
• Hypotonic solutions (lower osmotic pressure than blood plasma) can cause RBC haemolysis (irreversible, fatal).
• Hypertonic solutions (higher osmotic pressure than blood plasma) can cause RBC shrinkage/pain to tissues.

Hypertonic Parenteral Solutions

• Hypertonic solutions: made isotonic through dilution.
• Suitable for IM or SC injection; slightly painful.
• IV infusions need slow injection or central catheterization.

Hypotonic Parenteral Solutions

• Made isotonic by adding electrolytes (e.g., sodium chloride) or osmotic agents (e.g., mannitol, glucose).
• Mannitol and glucose can be incompatible with some medications.
• Made isotonic by mixing with an isotonic saline solution (0.9% NaCl).

Tonicity Adjustment

• Amount of solute/dilution can be calculated using various methods: freezing point depression, sodium chloride equivalent, molar concentrations, serum osmolarity.

Lecture Quiz

• Compare SVP and LVP solutions regarding sterility, clarity, absence of pyrogens, buffer use, non-neutral solutions, hypotonic/hypertonic injections.

Components of Parenteral Products

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

Packaging (Containers)

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

Packaging Materials

• Glass.
• Rubber.
• Plastic.

Ampoules

• Single-dose glass containers for SVP.
• Glass neck designed for scratching/self-breaking.
• Glass particles may leach into the solution (filled under vacuum).

Vials

• Multi-dose and single-dose SVPs (1–100 ml).
• Glass bottle with rubber cap and sealed aluminum cap/plastic cover..
• Rubber materials (natural or synthetic, e.g., butyl rubber).

Vials (Limitations)

• Incomplete sealing of multi-dose vials leads to potential air contamination.
• Release of rubber particles.
• Adsorption of injection components (preservatives).

Pre-filled Syringes

• Overcomes particle release and air contamination problems.
• Expensive; requires special machines.

Plastic Containers

• LVP single-dose IV infusion bottles (100–1000 ml).
• Polymer (Polyethylene/polypropylene/PVC) + additives (plasticizers/opacifiers).
• Handling/transportation advantages.
• Drawbacks: Leaching (some drugs like fat emulsions/certain anticancer drugs leach plasticizers).
• Adsorption of certain medications, like nitroglycerin, on PVC.
• Low clarity and low visual inspection rating.

Flexible (PVC) and Semi-Rigid (PE) Plastic Containers

• Flexible PVC: can absorb some drugs (like nitroglycerin); no need for air tubes because solution drains by gravity.
• Semi-Rigid PE: more compatible; requires solution aeration to drain.

Glass Bottles

• Transparent; chemically inert.
• Can be used with incompatible materials (plastic).
• Disadvantages: breakage during transportation/handling.
• Needs aeration tubes for proper use.

Glass Bottles (cont.)

• Composition: Silicone dioxide + other oxides (e.g., soda-lime glass – Type III, sulphated glass - Type II)
• Type III glass releases alkali with water; not for aqueous solutions.
• Type II glass treated with sulfur oxides.
• Type I glass (SiO2 + boron oxide); multiple use, expensive.
• Type II glass cannot be reused.

Solvents for Injection

• Aqueous solvents: Water for injections (WFI).
• Non-aqueous solvents: Oil (e.g., fixed vegetable oils — corn oil, peanut oil, cottonseed oil, etc).
• Co-solvents (water-miscible): Glycerin, ethyl alcohol, propylene glycol (and PEG 300).

Water for Injection (WFI)

• Potable water is often contaminated with microorganisms, particles, dissolved gases, or minerals.
• WFI: is completely free of pyrogens and high chemical purity.
• Used in preparation of parenteral products.

Water for Injection (WFI) (cont.)

• Can be prepared by distillation, filtration, chemical softening, deionization, pH adjustment.
• Reverse osmosis can be used to obtain WFI.

SWFI and Bacteriostatic Water for Injection

• SWFI (sterile water for injection): packed in sealed containers (single dose), sterilized by moist heat and used to dilute or dissolve before injection.
• Bacteriostatic water for injection: SWFI with a bacteriostatic agent (used for multi-dose containers).

Co-solvents

• Water-miscible solvents mixed with water in some parenteral preparations to improve drug solubility and stability.
• Common co-solvents include glycerin, ethyl alcohol, propylene glycol, and PEG 300.
• Higher concentrations of ethanol can be toxic/irritant/painful.

Non-Aqueous Solvents (Oils)

• Used to solubilize drugs (e.g., digoxin).
• Stabilize water-hydrolysable drugs (e.g., barbiturates).
• Provide sustained effect for drugs like steroids.
• Often fixed vegetable oils.

Additives

• Antimicrobials, buffers, tonicity adjusters, antioxidants, surfactants.

Antioxidants

• Added for stability.
• Preferentially oxidized throughout the shelf life.
• Examples: Ascorbic acid, cysteine, sodium metabisulfite, tocopherol.

Surfactants

• Used in parenteral suspensions for wetting and to prevent crystal growth.
• Useful in parenteral emulsions.
• Examples include sorbitan monooleate, and polyoxyethylene sorbitan monooleate.

Production of Parenteral Solutions

• Sterile environments (high-standard clean rooms) are essential.
• Production mistakes lead to contamination.
• Contamination sources include raw materials, personnel (training/hygiene), and the production area (sterile rooms/HEPA filters).

Raw Materials

• Special grades (pyrogen free) are required for injections.

Personnel

• Requires high degree of training.
• High personnel hygiene.
• Sterile, fiber-free clothing to prevent contamination.

Production Area

• Sterile rooms with laminar flow hoods and HEPA filters are used.
• Air is filtered to remove particles (>0.3 µm) and microbial contaminants.

Note that (Laminar Flow)

• Laminar flow is a technique that maintains an area free from particles and microbial contaminants (not sterilization).
• IV admixtures are created when one or more sterile products are added to an IV fluid.
• Mixing/preparation of IV admixtures should be conducted in aseptic environments.

Quality Control Testing and Evaluation (BP)

• Container tests.
• Whole batch tests.
• Sample tests.
• Compendial methods (required to be followed).

Container Tests

• Glass containers.
• Plastic containers.
• Rubber closures:
• Glass alkalinity tests
  • Surface alkalinity.
  • Powdered glass alkalinity.
• Plastic container leaching tests.
• Rubber closure tests (leaching, permeability).
• Resealing.
• Fragmentation.

Whole Batch Tests

• Leaker tests (for ampoules).
• Clarity tests (visual inspection for particles).

Sample Tests

• Sterility tests (part of microbiology): checks for absence of microorganisms.
• Pyrogen tests (e.g., Rabbit pyrogen test).
• Bacterial endotoxin test (LAL test).
• Extractable volume test.
• Clarity test for sub-visible particles (measuring particles).
  • Direct measurement (e.g., particle count).
  • Microscopical measurement (filtration to view particle size/number).

Pyrogen Testing

• Biological test: Rabbit pyrogen test:
  • Qualitative.
  • Injected IV solution into 3 rabbits; measure body temperature increase.
  • Pyrogenic solutions elevate body temperature within 3 hours.
  • Increase in each rabbit should be <0.6°C; total increase in all rabbits should be <1.4°C.
• Advantages: reaction similar to humans, can detect all pyrogens.
• Disadvantages: expensive, time-consuming, less sensitive.

Bacterial Endotoxin Test (LAL)

• In vitro/easier & more rapid/inexpensive.
• Gel formation is dependent upon the presence of pyrogens in a reagent.
• LAL reagent contains clotting proteins, while pyrogens assist in the clotting process.
• Detects pyrogens from Gram-negative bacteria (more dangerous/common), not those of Gram-positive or pyrogenic material.
• Many factors may affect results (pH, ions in solution).

Test your knowledge on various pharmaceutical classifications, formulations, and their characteristics. This quiz covers topics like routes of administration, types of sterile preparations, and advantages and limitations of parenteral preparations. Challenge yourself to match descriptions accurately!