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Questions and Answers
Which of the following methods is NOT a pre-treatment for feed water used in the preparation of WFI?
Which of the following methods is NOT a pre-treatment for feed water used in the preparation of WFI?
Bacteriostatic water for injection can only be used for single doses.
Bacteriostatic water for injection can only be used for single doses.
False (B)
What are two common water-miscible solvents used in parenteral preparations?
What are two common water-miscible solvents used in parenteral preparations?
Glycerin, Ethyl alcohol
The major class of non-aqueous solvents used for injections are __________.
The major class of non-aqueous solvents used for injections are __________.
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Match the following additives with their purpose:
Match the following additives with their purpose:
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Which type of sterilization method uses heat to eliminate microorganisms?
Which type of sterilization method uses heat to eliminate microorganisms?
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Preservatives are added to single-dose containers to protect against contamination.
Preservatives are added to single-dose containers to protect against contamination.
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What is an ideal characteristic of a preservative for multi-dose injections?
What is an ideal characteristic of a preservative for multi-dose injections?
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Pyrogens are fever-producing _____ found in the outer membrane of Gram-negative bacteria.
Pyrogens are fever-producing _____ found in the outer membrane of Gram-negative bacteria.
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Match the preservative to its concentration range:
Match the preservative to its concentration range:
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Which of the following is a common source of pyrogens?
Which of the following is a common source of pyrogens?
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Why must parenteral solutions be free of foreign particles?
Why must parenteral solutions be free of foreign particles?
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Which characteristic of pyrogens allows them to pass through bacterial filters?
Which characteristic of pyrogens allows them to pass through bacterial filters?
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What is the accepted pH range for non-neutral large volume parenterals (LVP)?
What is the accepted pH range for non-neutral large volume parenterals (LVP)?
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All pyrogens can be effectively eliminated by simple rinsing with water.
All pyrogens can be effectively eliminated by simple rinsing with water.
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Hypertonic solutions can cause irreversible hemolysis of red blood cells when injected IV.
Hypertonic solutions can cause irreversible hemolysis of red blood cells when injected IV.
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What are the two main methods of depyrogenation mentioned for packing materials?
What are the two main methods of depyrogenation mentioned for packing materials?
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What is the main purpose of using hypertonic solutions in some patient cases?
What is the main purpose of using hypertonic solutions in some patient cases?
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Pyrogens become a concern when injected because they can activate the _____ system, leading to shock.
Pyrogens become a concern when injected because they can activate the _____ system, leading to shock.
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Match the following depyrogenation methods with their descriptions:
Match the following depyrogenation methods with their descriptions:
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Hypotonic parenteral solutions can be made isotonic by adding __________.
Hypotonic parenteral solutions can be made isotonic by adding __________.
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Match the following types of solutions with their effects on tissues:
Match the following types of solutions with their effects on tissues:
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What is the ideal pH of parenteral preparations?
What is the ideal pH of parenteral preparations?
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Injectable drugs should always have a neutral pH of 7.4.
Injectable drugs should always have a neutral pH of 7.4.
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What happens when a non-neutral LVP is injected too quickly?
What happens when a non-neutral LVP is injected too quickly?
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What is a common reason to use buffers in non-neutral SVP formulations?
What is a common reason to use buffers in non-neutral SVP formulations?
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The osmotic pressure is the pressure needed to prevent water from moving to a salt solution.
The osmotic pressure is the pressure needed to prevent water from moving to a salt solution.
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What key characteristic do parenteral preparations need to have?
What key characteristic do parenteral preparations need to have?
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The acceptable pH range for non-neutral SVP for tissues is _____ to _____ for non-intravenous routes.
The acceptable pH range for non-neutral SVP for tissues is _____ to _____ for non-intravenous routes.
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Injecting hypertonic solutions via __________ can reduce pain during the administration.
Injecting hypertonic solutions via __________ can reduce pain during the administration.
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Which of the following is a consequence of injecting hypotonic solutions?
Which of the following is a consequence of injecting hypotonic solutions?
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What is a major disadvantage of using PVC containers for drug storage?
What is a major disadvantage of using PVC containers for drug storage?
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Type II glass can be reused multiple times without any changes to its internal surface.
Type II glass can be reused multiple times without any changes to its internal surface.
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What is the primary composition of Type I glass?
What is the primary composition of Type I glass?
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The highest proportion of a formulation used for injections is made up of ______.
The highest proportion of a formulation used for injections is made up of ______.
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Match the type of glass with its properties:
Match the type of glass with its properties:
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Which of the following is a non-aqueous solvent?
Which of the following is a non-aqueous solvent?
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Glass bottles are chemically inert and can be safely used with incompatible materials.
Glass bottles are chemically inert and can be safely used with incompatible materials.
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What is the primary advantage of using glass bottles for drug storage?
What is the primary advantage of using glass bottles for drug storage?
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Water for injection (WFI) is free of ______ and of high chemical purity.
Water for injection (WFI) is free of ______ and of high chemical purity.
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What characteristic of flexible PVC bags allows for drainage by gravity?
What characteristic of flexible PVC bags allows for drainage by gravity?
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Study Notes
Sterile Pharmaceutical Preparations
- Sterile preparations include parenteral preparations, ophthalmic preparations, dialysis solutions/irrigation solutions, radiopharmaceuticals, and plasma expanders.
Parenteral Preparations
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Definition: Para = beyond; entrone = intestine. Sterile dosage forms delivered to the patient externally (bypassing the alimentary canal). Parenteral preparations are sterile solutions intended for administration by injection, infusion, or implantation into human or animal bodies.
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Types of injections: Intramuscular (IM), Intravenous (IV), Subcutaneous (SC), Intradermal (ID), Intraspinal (Intrathecal), Intraperitoneal (IP). Specific volumes are associated with each route(e.g., IM injections typically up to 5ml, SC - insulin typically 1.5ml).
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Advantages: Suitable for drugs with instability in the GIT, drugs with poor GIT absorption, GIT irritating drugs, unconscious or uncooperative patients, rapid correction of fluid/electrolyte imbalances, and for nauseated patients. Offers shorter onset of action and lower doses/side effects, and is suitable for drugs targeting specific organs.
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Disadvantages: Invasive and painful (lower compliance), traumatic injury from needle/catheter insertion, and mistakes (e.g. toxic dose, incorrect drug, or contaminants).
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IV injection vs. IV infusion: IV injection involves small volume parentrals (SVP) administered via syringe directly into the vein, while IV infusion uses large volume parentrals (LVP) via catheter directly to the blood stream.
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IV infusions can provide: Parenteral nutrition (PN)/total parenteral nutrition (TPN), correction of fluid/electrolyte imbalances, and administration of large doses of drugs (antibiotics, chemotherapy).
Classification of Parenterals
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Pharmaceutical classification: Solutions, suspensions, emulsions, and dry powders.
- Solutions can be aqueous (e.g., water, co-solvents, and used for IM & IV), or non-aqueous (e.g., oils).
- Suspensions are for insoluble in water drugs, via IM, prolonged (depot) effect, and a particle size range of 5-10 µm.
- Emulsions are O/W. Parenteral IV emulsions are uncommon.
- Dry powder is for unstable drugs in solution. Reconstitute before use (pharmacist aware of volume, form, and expiry).
- Volume based classification: Large volume parenterals (LVP) and Small volume parenterals (SVP)
How to Achieve Controlled Drug Delivery?
- Increasing particle size (suspension) and viscosity (oil solutions and suspensions or viscosity-imparting agents) ↓ drug dissolution rate, ↓ absorption rate, sustained effect
- Use of implants (solid sterile DF)
- Use of less soluble salts (Insulin-Zn)
- Use of crystalline rather than amorphous form (Insulin Lente)
Insulin Lente
- Insulin zinc suspension
- Intermediate-acting porcine or human insulin with zinc salt added, solid phase of the suspension contains a ratio of 7:3 (crystalline to amorphous insulin).
Assignments
- Assignment 1: Investigate different insulin formulations in the market with varying duration and onset of action.
- Assignment 2: Collect market examples of parenteral products (dry powder for reconstitution, oily injections, long-acting injections, and emulsion-based parenterals), including active constituents, different doses, labels (excipients), and reconstitution methods.
Specifications of Parenteral Preparations
- Sterility: Sterile preparations are completely free from microorganisms and contaminants. Presence of pathogens is serious (fatal in IV). Preservatives are used to maintain sterility.
- Clarity: Parenteral solutions are clear. Free of foreign particles (e.g., dust, glass, fiber). Foreign particles are non-biodegradable and accumulate in some ways (e.g., IM - muscle granuloma; IV - embolism/thrombosis).
- 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 (most common).
- Tonicity: Parenteral preparations should be isotonic. Same osmotic pressure as blood plasma. Solutions with OP less than plasma are hypotonic; greater are hypertonic.
- pH: Ideal pH of parenteral preparations is 7.4. However, some injected drugs require different pH values.
Methods of Sterilization
- Moist heat sterilization
- Dry heat sterilization
- Ionizing radiation sterilization
- Gaseous sterilization (ethylene oxide)
Preservation
- Antimicrobial agents are added to multi-dose vials to protect against contamination during production, use, and storage.
- Preservatives are not generally added to LVPs (single-dose containers discarded after opening).
- Preservatives should be effective against a wide range of bacteria, non-toxic at the use concentrations, stable, and compatible with injection components (no interaction).
- Specific examples of commonly used preservatives in multi-dose injections are given.
Clarity
- Parenteral solutions must be clear. Free of foreign particles (dust, glass, fiber) - Why? Foreign particles are non-biodegradable, accumulation in tissues depending on route (IM - muscle granuloma, IV - embolism/thrombosis).
Absence of Pyrogens
- Parenteral solutions must be non-pyrogenic (pyrogen-free).
- Pyrogens: Fever-producing endotoxins found in Gram-negative bacteria (outer membrane).
- Composition: Lipopolysaccharides (lipid A linked to a central polysaccharide core).
- Sources of pyrogens: Solvents (water), equipment, packing materials, and raw materials used in production.
- Biological activity: Injection of pyrogens can cause toxic effects. Contamination of LVPs can cause serious problems (lipid A affects thermoregulatory centers, high doses activate coagulation).
- Characteristics of pyrogens: Water-soluble, non-volatile, pass through bacterial filters, and heat-stable.
Depyrogenation
- Depyrogenation: Elimination of pyrogens from solvents, equipment, and raw materials. Removal or inactivation.
Water Depyrogenation
- Distillation (BP): Principle method to avoid water contamination with pyrogens (non-volatile).
- Reverse osmosis (USP): Filtration of water under high pressure using semi-permeable membrane removing substances and most ions.
- Ultrafiltration: Removes pyrogens from solutions.
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).
pH (cont)
- Ideal pH of parenteral preparations is 7.4.
- Some drugs require different pH values.
- Some are insoluble or unstable at pH 7.4.
Non-neutral SVP
- Formulate at suitable pH for stability/solubility.
- Add a buffer system of low buffering capacity.
- Allows rapid neutralization by natural buffer systems (e.g. Acetate, phosphate, citrate).
- Acceptable pH range in tissues is 4-9 (other/non-IV routes). Higher/lower values irritate/damage cells. Borate buffer use is forbidden.
Non-neutral LVP (cont)
- IV infusions should not contain buffering systems (large volume needs large of buffer quantity - toxicity concerns). To allow neutralization of a large volume of buffer with low buffer capacity it is difficult.
- IV infusions injected very slowly with low infusion rates. No change to blood pH by large volume (rapid neutralization). Avoid drug precipitation during injection in circulation (no sudden change to formulation pH).
- Acceptable pH range for non-neutral LVP is 3-10.5. Any change in blood pH can result in systemic acidosis or alkalosis (life-threatening).
Tonicity (osmotic pressure)
- If a semi-permeable membrane separates water from an electrolyte solution, water will pass from its compartment to the salt compartment.
- The required pressure to overcome water pressure is the osmotic pressure.
- Parenteral preparations are typically isotonic.
Components of Parenteral Products
- Container (Packaging): Glass ampoules, rubber stoppered vials, glass/plastic bottles, glass/plastic syringes, prefilled syringes.
- Active constituent: The drug being administered.
- Solvent: The liquid in which the active constituent is dissolved or suspended (e.g., water, co-solvents, oils).
- Additives: Chemicals added to the preparation to enhance stability, solubility, or other desirable properties (e.g., preservatives, buffers, tonicity adjusters, antioxidants, surfactants).
Packaging (Containers)
- Glass ampoules: Single-dose glass container for small volume parenterals (SVP), scratching glass neck releases.
- Rubber stoppered vials: Multi-dose, and single-dose SVP (1-100 ml), with rubber material and plastic cover.
- Glass/Plastic bottles: Containers for large volume parenterals (LVP)
- Glass/Plastic syringes: Syringes filled with solutions.
- Prefilled syringes: Overcome problems of particle release and air contamination, but are expensive, and require special machinery.
- Plastic containers: Single-dose IV infusion bottles (100-1000 ml) with materials, e.g., polymer (Polyethylene or polypropylene or PVC)
- Flexible PVC (e.g., plastic bags) Adsorbs some drugs (nitroglycerin), no air tube required, semi-rigid (PE), more compatible, Needs aeration for drainage.
- Glass bottles (Advantages) Transparent, chemically inert, used with incompatible materials with plastic, (Disadvantages) Breakage (transportation), Need for an aeration tube or needle.
- Glass (cont) Types III, II, and I glass.
Solvents for Injection
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Aqueous: Water, co-solvents.
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Non-aqueous: Oils such as corn oil, cottonseed ,peanut or sesame oil. Used for solubilization, stabilization, or sustained effects
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Grades of Water: Water for injection (WFI).
- Purified water
- Sterile water for injection (SWFI) containing bacteriostatic agent.
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Co-Solvents: Glycerin, ethyl alcohol, propylene glycol, and PEG 300.
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Non-aqueous solvents: Used for solubilization, stabilization, or sustained-release effects.
Additives (cont):
- Antimicrobial agents
- Buffers
- Tonicity adjusting agents
- Antioxidants
- Surfactants
Production of Parenteral Solutions
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High-standard clean rooms and environments are needed for manufacturing.
- Raw materials must be special grade and pyrogen-free.
- Production personnel need specialized training and hygiene maintenance. Special clothes.
- Production area needs sterile rooms fitted with laminar flow hoods and HEPA filters to remove microbial contaminants.
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Laminar flow: Only maintains an area free from particles and microorganisms.
Quality Control Testing and Evaluation (BP)
- Container tests: Glass containers, plastic containers, and rubber closures. (e.g., glass alkalinity, plastic leaching, rubber closure tests).
- Whole batch tests: Leaker test, clarity test.
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Sample tests: Sterility tests, pyrogen tests, extractable volume test, and clarity tests (sub-visible particles).
- Specific tests exist for each item (e.g. glass test).
Pyrogen testing (cont.):
- Advantages of Rabbit Pyrogen Test: Reaction similar to that in man; ability to detect all types of pyrogens.
- Disadvantages of Rabbit Pyrogen Test: Expensive, time-consuming, low sensitivity, interference from injection components.
- Advantages of LAL Test: Rapid, inexpensive, quantitative determination of endotoxins, and is good as a test for Gram-negative pyrogens.
- Disadvantages of LAL Test: Results can be affected by factors such as pH and ions, it doesn't detect pyrogens of gram positive bacteria.
Extractable volume test
- Measure the volume that can be extracted from the container (should not be lower than labeled volume).
Clarity test for sub-visible particles.
- Direct measurement and microscopical measurement
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Description
Test your knowledge on pharmaceutical preparations, focusing on water for injection (WFI), sterilization methods, and preservatives in parenteral solutions. This quiz covers key concepts essential for understanding the requirements and processes involved in preparing safe and effective medications.
