Pharmaceutical Preparation and Testing Quiz

Sterile Pharmaceutical Preparations

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

Parenteral Preparations

• Parenteral preparations are sterile dosage forms delivered outside the alimentary canal.
• Definitions: Para = beyond, enteron = intestine.
• Parenteral preparations are sterile preparations intended for administration by injection, infusion, or implantation into human or animal bodies.

Parenteral Preparations Details

• Includes introduction and definitions, advantages and limitations, types of injections, classifications of injections, specifications and requirements, components of parenteral products, production process, and compendia quality control testing.

Types of Injections

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

IV Injection vs. Infusion

• IV Injection: administration of small volume parenterals (SVP) medications by syringe directly into the vein.
• IV Infusion: administration of large volume parenterals (LVP) via a catheter into the vein directly to the blood stream.

Advantages of IV Infusion

• Providing parenteral nutrition (PN) and total parenteral nutrition (TPN) for hospitalized patients.
• Correcting fluid or electrolyte imbalances.
• Administering large doses of drugs (e.g., antibiotics, chemotherapy) continuously.

Advantages of Parenteral Preparations

• Useful for drugs with instability in the gastrointestinal tract (GIT): insulin, heparin, and streptomycin.
• Useful for drugs with poor GIT absorption.
• Useful for GIT irritating drugs.
• Useful for unconscious or uncooperative patients.
• For rapid correction of fluid and electrolyte imbalances.
• Faster onset of action (emergency).
• Lower dose and side effects in some cases.
• Useful for administering drugs targeting specific organs.

Limitations of Parenteral Preparations

• Invasive and painful (lower compliance).
• Traumatic injury from insertion of needles or catheters.
• Difficulty in treating mistakes (toxic doses, incorrect drugs, or contaminants).

Classification of Parenterals

• Pharmaceutical classification: Solutions, suspensions, emulsions, dry powder.
• Volume-based classification: Large volume parenterals (LVP), Small volume parenterals (SVP).

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 container for SVP.
• Glass neck must be scratched (or self-breaking).
• May release glass particles into solution (filled under vacuum).

Vials

• Multi-dose and single-dose SVP (1–100 ml).
• Glass bottle with rubber cap and aluminum seal covered with plastic cover.
• Rubber material may include natural or synthetic (butyl rubber).
• Limitations: Incomplete sealing, air contamination, release of rubber particles, adsorption of injection components (preservatives).

Additional Information

• Pre-filled syringes: overcome particle release and air contamination but is expensive and needs special equipment.
• Plastic containers: LVP, single-dose IV infusion bottles (100–1000 ml), polymer (polyethylene, polypropylene, or PVC), additives (plasticizer, opacifier), advantages (handling, transportation), disadvantages (leaching, adsorption).
• Flexible (PVC): absorbs some drugs (e.g. nitroglycerin), no need for air tubing in some cases.
• Semi-Rigid (PE): more compatible, but needs solution aeration for drainage.

Glass Bottles

• Advantages: Transparent, chemically inert, compatible with materials incompatible with plastic.
• Disadvantages: Breakage, need for aeration tube/needle. Also, different types of glass have different properties (Type I: no release of alkalinity, used more often; Type II: alkalinity release).

Solvents for Injection

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

Water for Injection (WFI)

• Potable water may include contamination with: organisms, particles, gases, or minerals.
• WFI is completely free of pyrogens and high chemical purity.

WFI Preparation

• Distillation (BP), filtration, chemical softening, deionization, pH adjustment, reverse osmosis.

Additional Water for Injection Types

• SWFI: packed in sealed containers (single dose) - sterilized by moist heat.
• Bacteriostatic water for injection: contains a bacteriostatic agent (multi-dose).

Co-solvents

• Water-miscible solvents mixed with water in some parenteral preparations (e.g., glycerin, ethyl alcohol, propylene glycol, and PEG 300), commonly enhance drug solubility, or stabilize drugs.
• Higher concentrations of some co-solvents (e.g., ethanol) may be toxic, irritant, and painful.

Non-aqueous Solvents (Oils)

• Solubilization (e.g. digoxin).
• Stabilization (e.g. barbiturates).
• Sustained effect (e.g. steroids)

Additives

• Antimicrobial agents, buffers, tonicity adjusting agents, antioxidants, surfactants.

Antioxidants

• Added for stability purposes.

Surfactants

• Used in parenteral suspensions for wetting, crystal growth prevention, and good syringeability.
• Used in parenteral emulsions.

Production of Parenteral Solutions

• Preparation and filling in clean room environments.
• Raw materials, personnel, and production areas must meet standards to prevent particulate, organism, and pyrogen contamination.

Quality Control Testing and Evaluation (BP)

• I. Tests for container; II. Tests for whole batch; III. Tests for samples of the batch.
• A. Glass test (glass alkalinity).
• B. Test for plastic containers (leaching).
• C. Test for rubber closure (releasing materials, permeability).

Pyrogen Testing:

• Qualitative test: Inject the tested solution to 3 rabbits and measure the increase in rabbit body temperature in 3 hours.
• Increase in body temperature in each rabbit should not exceed 0.6°C.
• Average increase in body temperature for all 3 rabbits should not exceed 1.4°C.

Bacterial Endotoxin Test (LAL test)

• In-vitro test, dependent on gel formation of LAL reagent when pyrogens are added.
• Advantages: rapid, inexpensive.
• Disadvantages: affects by pH, ions, and some positive bacteria/pyrogens might not be detected.

Extractable Volume Tests

• Measures the volume extract from a container.
• Should not be lower than the labeled volume.
• Clarity test for sub-visible particles: direct and microscopical measurement.

Miscellaneous

• Additional assignments were provided which cover the need to investigate different formulations of insulin on the market with varying duration and onset of actions. An additional assignment required to collect market examples of different pharmaceutical forms of parenteral products.
• Sterility, clarity, absence of pyrogens, use of buffers, and injection of non-neutral, hypotonic, and hypertonic solutions.
• Tonicity: isotonicity with respect to blood plasma is critical. Hypertonic solutions can be made isotonic by dilution. Hypotonic solutions can be made isotonic by adding electrolytes or osmotic agents (mannitol or glucose).
• Methods for tonicity adjustment include freezing point depression method, sodium chloride equivalent method, molar concentration method, and serum osmolarity method.